eBriefing

Sixth International Congress on Shwachman-Diamond Syndrome

Sixth International Congress on Shwachman-Diamond Syndrome
Reported by
Alan Dove

Posted August 31, 2011

Presented By

Presented by the New York Academy of Sciences

Overview

Shwachman-Diamond Syndrome, also known as Shwachman-Bodian-Diamond syndrome (SDS), is a rare disease that defies brief description. Though physicians generally think of SDS as an autosomal recessive genetic condition affecting blood cell production and the pancreatic, skeletal, and nervous systems, researchers who study it will quickly point out that it may not be exclusively genetic, and may affect many other organs. Indeed, even determining which patients have SDS and which do not is a complex exercise.

From June 28–30, 2011, the Sixth International Congress on Shwachman-Diamond Syndrome convened at the New York Academy of Sciences, featuring presentations from the leading scientists and physicians worldwide who study this baffling disease. During the three-day meeting, attendees learned about the clinical features and pathogenesis of SDS, the latest progress in unraveling the biology of the condition, and new diagnostic and treatment strategies.

About 90% of patients with SDS carry mutations in both copies of a gene called SBDS. Individuals with only one mutated SBDS gene are usually silent carriers. In recent years, biologists have determined that SBDS encodes a highly conserved protein required for ribosomes to mature. Patients with SDS usually produce insufficient amounts of pancreatic enzymes, leading to digestive problems, and develop specific immunological problems such as a shortage of neutrophils and an elevated rate of certain leukemias. They also tend to have short stature and cognitive problems.

Like most research, studies on SDS have raised as many questions as they have answered. Presenters at the meeting pondered why some patients with apparently normal SBDS genes still develop SDS, how the disease phenotype varies from one patient to the next, and how novel animal models can illuminate the activity of normal and mutant SBDS protein. One enduring problem is how alterations in such a fundamental molecular process—ribosomes are required for translating genes into proteins—can produce such a specific set of symptoms.

Physicians and scientists at the meeting also covered the latest thinking in the diagnosis and treatment of SDS. A panel discussion and workshop provided an overview of several international patient registries that are collecting data on affected individuals, several talks focused on the distinctive organ development problems that characterize the disease, and the conference's final session covered some promising laboratory results that could soon reach the clinic. A poster session and extensive discussions after the presentations gave the group ample opportunities to mull related problems. Though SDS still causes considerable difficulty for patients and their families, attendees were optimistic, not only about addressing this rare genetic condition, but also about using the new findings to inform treatment for more common maladies.

Use the tabs above to find a meeting report and multimedia from this event.

 

Presentations available from:

Stefano Biffo, PhD (San Raffaele Scientific Institute, Milan, Italy)
Paul de Figueiredo, PhD (Texas A&M University and Texas A&M Health Science Center)
Peter Durie, MD, FRCPC (The Hospital for Sick Children, the University of Toronto, Toronto, Canada)
Paul S. Frenette, MD (Albert Einstein College of Medicine)
Arlen W. Johnson, PhD (University of Texas at Austin)
Gerard Karsenty, MD, PhD (Columbia University College of Physicians and Surgeons)
Elizabeth N. Kerr, PhD (Hospital for Sick Children and University of Toronto, Toronto, Canada)
Steven D. Leach, MD (Johns Hopkins University School of Medicine)
Outi Mäkitie, MD, PhD (Children's Hospital, University of Helsinki, Helsinki, Finland)
Umadas Mâitra, PhD, DSc (Albert Einstein College of Medicine)
Johanna Rommens, PhD (University of Toronto and Hospital for Sick Children, Toronto, Canada)
David T. Scadden, MD (Massachusetts General Hospital and Harvard University)
Marina E. Tourlakis (Hospital for Sick Children and University of Toronto, Toronto, Canada)
Sanna Toiviainen-Salo, MD, PhD (University Central Hospital, Helsinki, Finland)
Alan J. Warren, MD, PhD (University of Cambridge, Cambridge, UK)


Presented by

  • The New York Academy of Sciences

Gold Sponsor

  • The Shwachman Diamond Project

Bronze Sponsors

Aptalis Pharma

Italian Association of Shwachman Syndrome

Shwachman-Diamond Syndrome Foundation

Shwachman-Diamond Syndrome Canada

Steven & Alexandra Cohen Children's Medical Center of New York

The Leukemia & Lymphoma Society

The Mushett Family Foundation

Academy Friends

Anonymous

Shwachman-Diamond America

Shwachman-Diamond Syndrome Support Holland

Grant Support

The project described is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, and the National Heart, Lung, and Blood Institute. The content of this program is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Pancreatic Defects in Shwachman-Diamond Syndrome


Peter Durie (Hospital for Sick Children and University of Toronto)
  • 00:01
    1. Introduction; Establishing diagnosis
  • 07:00
    2. Defining pancreatic phenotype; SDS and fat absorption; Clinical diagnosis
  • 12:37
    3. Trypsinogen and pancreatic isoamylase diagnosis; Study
  • 18:10
    4. Relationships between genotypes and pancreatic phenotype; Stature and skeletal
  • 20:30
    5. Summary and acknowledgement

Advances in Imaging Studies of Shwachman-Diamond Syndrome


Sanna Toiviainen-Salo (University Central Hospital, Helsinki)
  • 00:01
    1. Introduction; Multiorgan imaging; Tools
  • 7:00
    2. New methods and applications
  • 11:02
    3. MRI and SDS; Summary and conclusio

Understanding Neurocognitive Functioning in SDS


Elizabeth N. Kerr (Hospital for Sick Children and University of Toronto)
  • 00:01
    1. Introduction; Review of neurodevelopmental challenges
  • 10:25
    2. Developmental trajectory
  • 14:10
    3. Underlying neuromechanisms
  • 17:31
    4. Future approaches; Conclusions and acknowledgement

Genetics & Disease Models of Shwachman-Diamond Syndrome


Johanna Rommens (Hospital for Sick Children and University of Toronto)
  • 00:01
    1. Introduction; SBDS and SBDSP
  • 07:07
    2. Sbds and translation; Ribosomal diseases; Mouse models and study results
  • 19:17
    3. TP53 deficiency and premature brain death; Summary
  • 24:43
    4. Acknowledgements and conclusio

Cytoplasmic Maturation of the Ribosome


Arlen W. Johnson (University of Texas at Austin)
  • 00:01
    1. Introduction; The ribosome and translation
  • 05:28
    2. The pathway of cytoplasmic maturation; The release of Tif6
  • 15:16
    3. Rpl10 and the P-site tRNA; Efl1 and P-site loop mutants; "Test drive"
  • 23:05
    4. Acknowledgements and conclusio

Uncoupling of GTP Hydrolysis from eIF6 Release on the Ribosome Causes SDS


Alan J. Warren (University of Cambridge)
  • 00:01
    1. Introduction; SDS and ribosome maturation
  • 02:48
    2. SBDS and eIF6 release; SBDS and EFL1 cooperation
  • 10:03
    3. How the SBDS protein works
  • 17:00
    4. Towards novel therapeutics; Acknowledgements and conclusio

eIF6 and 60S Ribosome Biogenesis


Umadas Mâitra (Albert Einstein College of Medicine)
  • 00:01
    1. Introduction
  • 04:02
    2. eIF6 and 60S ribosome biogenesis; Phosphorylation in mammalian and yeast cells
  • 09:30
    3. Nucleo-cytoplasmic shuttling of proteins; Ser 174 and Ser 175
  • 14:42
    4. Sequence motif LQVP and calcineurin; Model
  • 21:30
    5. Conclusions and acknowledgement

Modulation of eIF6 Binding to 60S Subunits: Effects and Search for Modulators


Stefano Biffo (San Raffaele Scientific Institute, Milan)
  • 00:01
    1. Introduction
  • 03:54
    2. eIF6 is highly regulated; Knockout mouse studies
  • 10:27
    3. Gene signature of eIF6 het mice; Transformation and cancer
  • 14:45
    4. Screening eIF6 antagonists; Cautions; Conclusio

The Hematopoietic Stem Cell Microenvironment


Paul S. Frenette (Albert Einstein College of Medicine)
  • 00:01
    1. Introduction; The stem cell niche
  • 04:48
    2. Circadian fluctuations and homing
  • 12:03
    3. The neuro-reticular complex; Nestin+ studies
  • 19:28
    4. Cell trafficking; Marcophage depletion study; Conclusio

22nd Annual Jason Bennette Memorial Lecture: Bone Marrow Stromal Cell Dynamics


David T. Scadden (Massachusetts General Hospital and Harvard University)
  • 00:01
    1. Introduction
  • 02:44
    2. Mesenchymal lineages; Effects of Dicer1 deletion
  • 10:00
    3. Models of oncogenesis; Clinical support; Effects of SBDS deletion
  • 15:17
    4. Niche initiated dysplasia and neoplasia; Mx-1 and Mx1+ cells
  • 24:42
    5. Conclusions; Implications of niche oncogenesis model
  • 28:02
    6. Stroma as a regulator of tissue maintenance; Acknowledgement

Pancreas Development in Mouse and Zebrafish (and Man)


Steven D. Leach (Johns Hopkins University School of Medicine)
  • 00:01
    1. Introduction
  • 05:54
    2. Pancreatic development in the mouse
  • 10:45
    3. Pancreatic development in the zebrafish
  • 18:23
    4. Progenitor cells in the adult vertebrate pancreas
  • 22:53
    5. Acknowledgements and conclusio

Modeling Pancreatic Phenotypes of SDS in the Mouse


Marina E. Tourlakis (Hospital for Sick Children and University of Toronto)
  • 00:01
    1. Introduction; SDS pancreas model and Sbds function
  • 08:20
    2. Reduction of digestive enzyme expression; Loss of Sbds function
  • 16:05
    3. SDS pancreas dysplasia; Theorizing translation imapairment
  • 17:50
    4. Summary; Acknowledgements and conclusio

Shwachman-Diamond Syndrome Skeletal Phenotype


Outi Mäkitie (Children's Hospital, University of Helsinki)
  • 00:01
    1. Introduction; Skeletal dysplasias
  • 08:35
    2. SDS osteoporosis; Sbds ablation study
  • 17:06
    3. Bone growth and maintenance; SDS skeletal phenotype
  • 19:24
    4. Acknowledgements and conclusio

The Novel Endocrinology of Bones


Gerard Karsenty (Columbia University College of Physicians and Surgeons)
  • 00:01
    1. Introduction and hypothesis
  • 02:42
    2. Leptin and bone growth; Brain-derived serotonin; Study
  • 14:00
    3. Osteoporosis pseudoglioma and high bone mass syndrome; Lrp5 and Tph1; Study
  • 25:00
    4. Summary; Acknowledgements and conclusio

HDAC Inhibition in SDS Disease Models


Paul de Figueiredo (Texas A&M University and Texas A&M Health Science Center)
  • 00:01
    1. Introduction; Baker's yeast as discovery platform
  • 04:37
    2. Screening data; Trichostatin A; HDAC targets and inhibitors
  • 12:21
    3. Shimamura lab data; Relationship between SBDS and HDAC; Overexpression suppression
  • 19:35
    4. Inhibition of HDAC activity; Ribosome biogenesis; Regulation of acetylome
  • 21:50
    5. Summary and acknowledgement

Journal Articles

Blanche P. Alter

Dale DC, Bolyard AA, Schwinzer BG, et al. The severe chronic neutropenia international registry: 10-Year follow-up report. Support Cancer Ther. 2006;3(4):220-231.

Gadalla SM, Cawthon R, Giri N, Alter BP, Savage SA. Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes. Aging (Albany NY) 2010;2(11):867-874.

Rochowski A, Sun C, Glogauer M, Alter BP. Neutrophil functions in patients with inherited bone marrow failure syndromes. Pediatr. Blood Cancer 2011;57(2):306-309.

Monica Bessler

Keller P, Debaun MR, Rothbaum RJ, Bessler M. Bone marrow failure in Shwachman-Diamond syndrome does not select for clonal haematopoiesis of the paroxysmal nocturnal haemoglobinuria phenotype. Br. J. Haematol. 2002;119(3):830-832.

Woloszynek JR, Rothbaum RJ, Rawls AS, et al. Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome. Blood 2004;104(12):3588-3590.

Stefano Biffo

Gallo S, Beugnet A, Biffo S. Tagging of functional ribosomes in living cells by HaloTag® technology. In Vitro Cell. Dev. Biol. Anim. 2011;47(2):132-138.

Miluzio A, Beugnet A, Grosso S, et al. Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth. Cancer Cell 2011;19(6):765-775.

Ricciardi S, Boggio EM, Grosso S, et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Genet. 2011;20(6):1182-1196.

William G. Cole

Mäkitie O, Susic M, Cole WG. Early-onset metaphyseal chondrodysplasia type Schmid associated with a COL10A1 frame-shift mutation and impaired trimerization of wild-type α1(X) protein chains. J. Orthop. Res. 2010;28(11):1497-1501.

Saarinen A, Saukkonen T, Kivelä T, et al. Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin. Endocrinol. (Oxf). 2010;72(4):481-488.

Paul de Figueiredo

Ancona V, Appel DN, de Figueiredo P. Xylella fastidiosa: a model for analyzing agricultural biosecurity. Biosecur. Bioterror 2010;8(2):171-182.

Qin Q, Pei J, Ancona V, et al. RNAi screen of endoplasmic reticulum-associated host factors reveals a role for IRE1alpha in supporting Brucella replication. PLoS Pathog. 2008;4(7):e1000110.

Qin Q, Luo J, Lin X, et al. Functional analysis of host factors that mediate the intracellular lifestyle of Cryptococcus neoformans. PLoS Pathog. 2011;7(6):e1002078.

Sabrina C. Desbordes

Bussmann LH, Schubert A, Vu Manh TP, et al. A robust and highly efficient immune cell reprogramming system. Cell Stem Cell 2009;5(5):554-566.

Placantonakis DG, Tomishima MJ, Lafaille F, et al. Enriched motor neuron populations derived from bacterial artificial chromosome-transgenic human embryonic stem cells. Clin. Neurosurg. 2009;56:125-132.

Schultz SS, Desbordes SC, Du Z, et al. Single-molecule analysis reveals changes in the DNA replication program for the POU5F1 locus upon human embryonic stem cell differentiation. Mol. Cell. Biol. 2010;30(18):4521-4534.

Ibrahim J. Domian

Zhou B, Ma Q, Rajagopal S, et al. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 2008;454(7200):109-113.

Jean Donadieu

Donadieu J, Michel G, Merlin E, et al. Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: experience of the French neutropenia registry. Bone Marrow Transplant 2005;36(9):787-792.

Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet. J. Rare Dis. 2011;6:26.

Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25(9):917-929.

Yigal Dror

Ambekar C, Das B, Yeger H, Dror Y. SBDS-deficiency results in deregulation of reactive oxygen species leading to increased cell death and decreased cell growth. Pediatr. Blood Cancer 2010;55(6):1138-1144.

Dror Y, Durie P, Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp. Hematol. 2002;30(7):659-669.

Hashmi SK, Allen C, Klaassen R, et al. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Clin. Genet. 2011;79(5):448-458.

Tsangaris E, Klaassen R, Fernandez CV, et al. Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations. J. Med. Genet. 2011.

Peter Durie

Beharry S, Ellis L, Corey M, Marcon M, Durie P. How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease? J. Pediatr. 2002;141(1):84-90.

Dror Y, Durie P, Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp. Hematol. 2002;30(7):659-669.

Toiviainen-Salo S, Mäyränpää MK, Durie PR, et al. Shwachman-Diamond syndrome is associated with low-turnover osteoporosis. Bone 2007;41(6):965-972.

Steven R. Ellis

Johnson AW, Ellis SR. Of blood, bones, and ribosomes: is Swachman-Diamond syndrome a ribosomopathy? Genes Dev. 2011;25(9):898-900.

Liu JM, Ellis SR. Ribosomes and marrow failure: coincidental association or molecular paradigm? Blood 2006;107(12):4583-4588.

Nihrane A, Sezgin G, Dsilva S, et al. Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A. Blood Cells Mol. Dis. 2009;42(1):85-91.

Paul S. Frenette

Dar A, Schajnovitz A, Lapid K, et al. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells. Leukemia 2011;25(8):1378.

Hashimoto D, Chow A, Greter M, et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 2011;208(5):1069-1082.

Magnon C, Lucas D, Frenette PS. Trafficking of stem cells. Methods Mol. Biol. 2011;750:3-24.

Arlen W. Johnson

Burwick N, Shimamura A, Liu JM. Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome. Semin. Hematol. 2011;48(2):136-143.

Lo K, Li Z, Bussiere C, et al. Defining the pathway of cytoplasmic maturation of the 60S ribosomal subunit. Mol. Cell 2010;39(2):196-208.

Villamonte R, Vehrs PR, Feland JB, et al. Reliability of 16 balance tests in individuals with Down syndrome. Percept. Mot. Skills 2010;111(2):530-542.

Gerard Karsenty

Confavreux CB, Borel O, Lee F, et al. Osteoid osteoma is an osteocalcinoma affecting glucose metabolism. Osteoporos. Int. 2011.

Inose H, Zhou B, Yadav VK, et al. Efficacy of serotonin inhibition in mouse models of bone loss. J. Bone Miner. Res. 2011.

Karsenty G, Gershon MD. The importance of the gastrointestinal tract in the control of bone mass accrual. Gastroenterology 2011;141(2):439-442.

Elizabeth N. Kerr

Kerr EN, Ellis L, Dupuis A, Rommens JM, Durie PR. The behavioral phenotype of school-age children with shwachman diamond syndrome indicates neurocognitive dysfunction with loss of Shwachman-Bodian-Diamond syndrome gene function. J. Pediatr. 2010;156(3):433-438.

Taco Kuijpers

Orelio C, Kuijpers TW. Shwachman-Diamond syndrome neutrophils have altered chemoattractant-induced F-actin polymerization and polarization characteristics. Haematologica 2009;94(3):409-413.

Orelio C, Verkuijlen P, Geissler J, van den Berg TK, Kuijpers TW. SBDS expression and localization at the mitotic spindle in human myeloid progenitors. PLoS ONE 2009;4(9):e7084.

Orelio C, van der Sluis RM, Verkuijlen P, et al. Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome. PLoS ONE 2011;6(6):e20727.

Steven Leach

Ghosh B, Leach SD. p53: Guardian of pancreatic epithelial identity. Cell Cycle 2011;10(11):1717.

Liu S, Leach SD. Zebrafish models for cancer. Annu. Rev. Pathol. 2011;6:71-93.

Rovira M, Scott S, Liss AS, et al. Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc. Natl. Acad. Sci. USA 2010;107(1):75-80.

M. William Lensch

Lensch MW, Rao M. Induced pluripotent stem cells: opportunities and challenges. Regen. Med. 2010;5(4):483-484.

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Zhu H, Lensch MW, Cahan P, Daley GQ. Investigating monogenic and complex diseases with pluripotent stem cells. Nat. Rev. Genet. 2011;12(4):266-275.

Jeffrey M. Lipton

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Lipton JM, Ellis SE, Vlachos A. Shwachman Diamond syndrome-phenotypes and genotypes: when clinical research informs biology. Pediatr. Blood Cancer 2008;51(4):449-450.

Tsai PH, Sahdev I, Herry A, Lipton JM. Fatal cyclophosphamide-induced congestive heart failure in a 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure treated with allogeneic bone marrow transplantation. Am. J. Pediatr. Hematol. Oncol. 1990;12(4):472-476.

Tsangaris E, Klaassen R, Fernandez CV, et al. Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations. J. Med. Genet. 2011.

Johnson M. Liu

Hashimoto D, Chow A, Greter M, et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 2011;208(5):1069-1082.

Nihrane A, Sezgin G, Dsilva S, et al. Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A. Blood Cells Mol. Dis. 2009;42(1):85-91.

Daniela Longoni

1. Minelli A, Maserati E, Nicolis E, et al. The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome. Leukemia 2009;23(4):708-711.

Umadas Mâitra

Basu U, Si K, Deng H, Mâitra U. Phosphorylation of mammalian eukaryotic translation initiation factor 6 and its Saccharomyces cerevisiae homologue Tif6p: evidence that phosphorylation of Tif6p regulates its nucleocytoplasmic distribution and is required for yeast cell growth. Mol. Cell. Biol. 2003;23(17):6187-6199.

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Outi Mäkitie

Mäkitie O, Susic M, Cole WG. Early-onset metaphyseal chondrodysplasia type Schmid associated with a COL10A1 frame-shift mutation and impaired trimerization of wild-type α1(X) protein chains. J. Orthop. Res. 2010;28(11):1497-1501.

Saarinen A, Saukkonen T, Kivelä T, et al. Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin. Endocrinol. (Oxf). 2010;72(4):481-488.

Toiviainen-Salo S, Pitkänen O, Holmström M, et al. Myocardial function in patients with Shwachman-Diamond syndrome: aspects to consider before stem cell transplantation. Pediatr. Blood Cancer 2008;51(4):461-467.

Elayne Provost

Kielhorn E, Provost E, Olsen D, et al. Tissue microarray-based analysis shows phospho-β-catenin expression in malignant melanoma is associated with poor outcome. Int. J. Cancer 2003;103(5):652-656.

Provost E, Yamamoto Y, Lizardi I, et al. Functional correlates of mutations in β-catenin exon 3 phosphorylation sites. J. Biol. Chem. 2003;278(34):31781-31789.

Provost E, McCabe A, Stern J, et al. Functional correlates of mutation of the Asp32 and Gly34 residues of β-catenin. Oncogene. 2005;24(16):2667-2676.

Yu Z, Weinberger PM, Provost E, et al. β-Catenin functions mainly as an adhesion molecule in patients with squamous cell cancer of the head and neck. Clin. Cancer Res. 2005;11(7):2471-2477.

Johanna Rommens

Kerr EN, Ellis L, Dupuis A, Rommens JM, Durie PR. The behavioral phenotype of school-age children with shwachman diamond syndrome indicates neurocognitive dysfunction with loss of Shwachman-Bodian-Diamond syndrome gene function. J. Pediatr. 2010;156(3):433-438.

Leung R, Cuddy K, Wang Y, Rommens J, Glogauer M. Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis. Blood 2011;117(6):2044-2053.

Rothbaum R, Perrault J, Vlachos A, et al. Shwachman-Diamond syndrome: report from an international conference. J. Pediatr. 2002;141(2):266-270.

David Scadden

Ferraro F, Celso CL, Scadden D. Adult stem cels and their niches. Adv. Exp. Med. Biol. 2010;695:155-168.

Lo Celso C, Scadden D. Isolation and transplantation of hematopoietic stem cells (HSCs). J. Vis. Exp. 2007;(2):157.

Scadden D. A NEAT way of regulating nuclear export of mRNAs. Mol. Cell 2009;35(4):395-396.

Russell Schachar

Crosbie J, Pérusse D, Barr CL, Schachar RJ. Validating psychiatric endophenotypes: inhibitory control and attention deficit hyperactivity disorder. Neurosci. Biobehav. Rev. 2008;32(1):40-55.

Laurin N, Lee J, Ickowicz A, et al. Association study for genes at chromosome 5p13-q11 in attention deficit hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008;147B(5):600-605.

Max JE, Keatley E, Wilde EA, et al. Anxiety disorders in children and adolescents in the first six months after traumatic brain injury. J. Neuropsychiatry Clin. Neurosci. 2011;23(1):29-39.

Akiko Shimamura

Burwick N, Shimamura A, Liu JM. Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome. Semin. Hematol. 2011;48(2):136-143.

Huang JN, Shimamura A. Clinical spectrum and molecular pathophysiology of Shwachman-Diamond syndrome. Curr. Opin. Hematol. 2010.

Wong TE, Calicchio ML, Fleming MD, Shimamura A, Harris MH. SBDS protein expression patterns in the bone marrow. Pediatr. Blood Cancer 2010;55(3):546-549.

Sanna Toiviainen-Salo

Saarinen A, Saukkonen T, Kivelä T, et al. Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin. Endocrinol. (Oxf). 2010;72(4):481-488.

Toiviainen-Salo S, Mäkitie O, Mannerkoski M, et al. Shwachman-Diamond syndrome is associated with structural brain alterations on MRI. Am. J. Med. Genet. A. 2008;146A(12):1558-1564.

Toiviainen-Salo S, Pitkänen O, Holmström M, et al. Myocardial function in patients with Shwachman-Diamond syndrome: aspects to consider before stem cell transplantation. Pediatr. Blood Cancer 2008;51(4):461-467.

Toiviainen-Salo S, Durie PR, Numminen K, et al. The natural history of Shwachman-Diamond syndrome-associated liver disease from childhood to adulthood. J. Pediatr. 2009;155(6):807-811.e2.

Alan J. Warren

Finch AJ, Hilcenko C, Basse N, et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25(9):917-929.

Menne TF, Goyenechea B, Sánchez-Puig N, et al. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nat. Genet. 2007;39(4):486-495.

Shammas C, Menne TF, Hilcenko C, et al. Structural and mutational analysis of the SBDS protein family. Insight into the leukemia-associated Shwachman-Diamond Syndrome. J. Biol. Chem. 2005;280(19):19221-19229.

Wong CC, Traynor D, Basse N, Kay RR, Warren AJ. Defective ribosome assembly in Shwachman-Diamond syndrome. Blood 2011.

Cornelia Zeidler

Dale DC, Bolyard AA, Schwinzer BG, et al. The severe chronic neutropenia international registry: 10-Year follow-up report. Support Cancer Ther. 2006;3(4):220-231.

Göhring G, Karow A, Steinemann D, et al. Chromosomal aberrations in congenital bone marrow failure disorders—an early indicator for leukemogenesis? Ann. Hematol. 2007;86(10):733-739.

Sauer M, Zeidler C, Meissner B, et al. Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2007;39(3):143-147.

Conference Co-Chairs

Johnson M. Liu, MD

The Feinstein Institute for Medical Research
e-mail | website | publications

Johnson M. Liu researches stem cell defects in Fanconi anemia (FA) and Schwachman-Diamond Syndrome (SDS) at the Feinstein Institute for Medical Research. These disorders share pathophysiologic features and though rare, can serve as human genetic models of hematopoietic failure and cancer predisposition. Liu received his medical training at the University of Michigan Medical School after which he did his internship at the Medical University of South Carolina following by his residency at the National Cancer Institute at the National Institutes of Health. His fellowship was with the National Heart, Lung & Blood Institute, and his specialties are Internal Medicine and Hematology.

Sridhar Mani, MD

Albert Einstein College of Medicine of Yeshiva University
e-mail | website | publications

Sridhar Mani is Professor in the Departments of Medicine and Genetics, where he specializes in oncology. He is also the Miriam Mandel Faculty Scholar in Cancer Research. His research concerns orphan nuclear receptors, which control nearly every major physiologic and biochemical process in eukaryotes—from cell metabolism to xenobiotic detoxification, cell differentiation, and cancer cell growth. In particular he works on one such receptor, the steroid and xenobiotic receptor (SXR), a key regulator of genes encoding drug metabolizing and transport proteins. His laboratory focuses on defining the role of SXR and other orphans by using novel and dynamic models of human pathophysiology in (i) xenobiotic metabolism and pharmacology and (ii) carcinogenesis, organogenesis and anticancer drug resistance.

 

Organizers

Elizabeth N. Kerr, PhD, CPsych

The Hospital for Sick Children, University of Toronto
e-mail | website | publications

Elizabeth Kerr was awarded her B.A.Sc. from the University of Guelph, her MA from Lakehead University, and PhD from the University of Calgary, following which she completed a CPA/APA accredited internship in Neuropsychology at the Children's Hospital of Western Ontario. She has been a clinical neuropsychologist at SickKids since 1995, and she holds an associate scientific appointment in the Division of Neurology at SickKids and an adjunct clinical academic appointment with the Department of Paediatrics at the University of Toronto. As a full time clinician, Kerr heads up the Epilepsy Classroom and provides neuropsychological assessment and consultation to the Epilepsy Classroom, the Epilepsy Surgery program and Metabolic Genetics. Her major research activities focus on neurocognitive and behavioral outcomes in medically intractable epilepsy and genetic conditions: (1) Neurocognitive and behavioural functioning in children treated for intractable epilepsy; (2) Neurodevelopment in Shwachman Diamond Syndrome; (3) Genetics of reading disabilities; (4) Understanding executive skills and social skills in Phenylketonuria; and (5) Atypical Cystic Fibrosis (CF).

Jeffrey M. Lipton, MD, PhD

Steven and Alexandra Cohen Children's Medical Center of New York
e-mail | website | publications

Jeffrey Lipton is an attending physician at the Steven and Alexandra Cohen Children's Medical Center. He is the Chief of pediatric hematology/oncology and stem cell transplantation, and he is a professor of pediatrics. His work focuses on stem cell transplantation in bone marrow, the cellular and molecular biology of stem cell abnormalities in inherited bone marrow failure and Langerhans cell histiocytosis. Before joining the Children's Medical Center, Lipton held a fellowship in pediatric hematology/oncology at Children's Hospital and the Dana Farber Cancer Institute in Boston. His performed his residency also at the Children's Hospital in Boston, and attended Saint Louis University School of Medicine for his MD and PhD training.

Outi Mäkitie, MD, PhD

Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
e-mail | website | publications

Outi Mäkitie received her MD degree from the University of Helsinki, Finland. Her MD PhD thesis examined clinical and genetic characteristics of cartilage-hair hypoplasia, a genetic skeletal disorder. After completing training in Pediatrics and Pediatric Endocrinology at the University of Helsinki she was a postdoctoral fellow from 2000 to 2003 in the laboratory of William G. Cole at the Hospital for Sick Children, University of Toronto. Her research in Toronto focused on several aspects of pediatric bone diseases, including genetic and clinical features of pediatric osteoporosis and skeletal dysplasias. After returning to Helsinki she joined the Helsinki University Central Hospital as the Head of Pediatric Endocrinology and Metabolic Bone Diseases and has continued active research on pediatric bone diseases.

Johanna Rommens, PhD

The Hospital for Sick Children, University of Toronto
e-mail | website | publications

Johanna Rommens is a Senior Scientist in Genetics and Genome Biology at the Research Institute of the Hospital for Sick Children and a Professor in the Department of Molecular Genetics at the University of Toronto. Her laboratory is interested in the mechanisms of genetic diseases and the generation of gene maps. In particular, she focuses on the routing of CFTR, a protein product that is affected in cystic fibrosis, using heterologous expression systems and site-directed mutagenesis in order to obtain a better understanding of how mutations lead to disease. She also conducts molecular genetic studies to identify the location of the affected gene in SDS, with the long-term goal of identifying the basic defect.

Akiko Shimamura, MD, PhD

Fred Hutchinson Cancer Research Center
e-mail | website | publications

Akiko Shimamura received her AB degree from Princeton University and her MD and PhD from the University of Rochester School of Medicine. She completed an internship and residency at Johns Hopkins Hospital and a fellowship at Children's Hospital Boston and Dana-Farber Cancer Institute. She was a Howard Hughes Medical Institute postdoctoral fellow prior to becoming an Assistant Professor of Pediatrics at Harvard Medical School. She served as director of the bone marrow failure clinic at Children's Hospital Boston.

Alan J. Warren, MD, PhD

University of Cambridge
e-mail | website | publications

Alan J. Warren trained in Biochemistry and medicine at the University of Glasgow, subsequently completing his haematology training at the Hammersmith Hospital in London. He gained his PhD in molecular biology at the MRC Laboratory of Molecular Biology (MRC-LMB) under the supervision of TH Rabbitts FRS. Warren established an essential role for the Lmo2 gene in haematopoiesis using gene targeting in murine embryonic stem cells. As an MRC Senior Clinical Fellow, Warren elucidated the DNA binding mechanism of the AML1-CBFβ transcription factor complex using X-ray crystallography. He was appointed as Professor of Haematology in the University of Cambridge in 2003 and is a Group Leader at the MRC Laboratory of Molecular Biology. The focus of his current research is the molecular mechanism underlying late cytoplasmic ribosome maturation and how perturbation of this process causes the leukaemia predisposition disorder Shwachman-Diamond syndrome (SDS). He runs the specialist bone marrow failure/MDS clinic at Addenbrooke’s Hospital, Cambridge and is Chairman of the Shwachman-Diamond UK Medical Advisory Board. Warren was elected Fellow of the Academy of Medical Sciences in 2005.


Speakers

Blanche P. Alter, MD, MPH

National Cancer Institute
e-mail | website | publications

Monica Bessler, MD, PhD

Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine
e-mail | website | publications

Stefano Biffo, PhD

San Raffaele Scientific Institute, Milan, Italy
e-mail | website | publications

William G. Cole, MBBS, PhD, FRCS(C)

University of Alberta, Edmonton, Canada
e-mail | website | publications

Paul de Figueiredo, PhD

Texas A&M University and Texas A&M Health Science Center
e-mail | website | publications

Sabrina C. Desbordes, PhD

Center for Genomic Regulation
e-mail | publications

Ibrahim J. Domian, MD, PhD

Harvard Medical School, Massachusetts General Hospital
e-mail | website | publications

Jean Donadieu, MD, PhD

Trousseau Hospital, Paris, France
e-mail | website | publications

Yigal Dror, MF, FRCP(C)

The Hospital for Sick Children, University of Toronto, Toronto, Canada
e-mail | website | publications

Peter Durie, MD, FRCP(C)

The Hospital for Sick Children, University of Toronto, Toronto, Canada
e-mail | website | publications

Steven R. Ellis, PhD

University of Louisville
e-mail | website | publications

Paul S. Frenette, MD

Albert Einstein College of Medicine of Yeshiva University
e-mail | website | publications

Arlen W. Johnson, PhD

The University of Texas at Austin
e-mail | website | publications

Gerard Karsenty, MD, PhD

Columbia University College of Physicians and Surgeons
e-mail | website | publications

Taco Kuijpers, MD, PhD

Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands
e-mail | publications

Steven Leach, MD

Johns Hopkins University School of Medicine
e-mail | website | publications

M. William Lensch, PhD

Children's Hospital Boston, Harvard Medical School
e-mail | website | publications

Daniela Longoni, MD

Clinica Pediatrica-Ospedale San Gerardo-Monza, Milan, Italy
e-mail | publications

Umadas Maitra, PhD, DSc

Albert Einstein College of Medicine of Yeshiva University
e-mail | website | publications

Elayne Provost, PhD

Johns Hopkins University
e-mail | website | publications

David Scadden, MD

Massachusetts General Hospital, Harvard University
e-mail | website | publications

Russell Schachar, MD, FRCP(C)

The Hospital for Sick Children, University of Toronto, Toronto, Canada
e-mail | website | publications

Sanna Toiviainen-Salo, MD, PhD

University Central Hospital, Helsinki, Finland
e-mail | publications

Marina E. Tourlakis

The Hospital for Sick Children, University of Toronto, Toronto, Canada
e-mailpublications

Cornelia Zeidler, MD

Hanover Medical School, Hanover, Germany
e-mail | publications


Alan Dove, PhD

Alan Dove is a science writer and reporter for Nature Medicine, Nature Biotechnology, and Bioscience Technology. He also teaches at the NYU School of Journalism, and blogs at http://dovdox.com.

Sponsors

Presented by

  • The New York Academy of Sciences

Gold Sponsor

  • The Shwachman Diamond Project

Bronze Sponsors

Aptalis Pharma

Italian Association of Shwachman Syndrome

Shwachman-Diamond Syndrome Foundation

Shwachman-Diamond Syndrome Canada

Steven & Alexandra Cohen Children's Medical Center of New York

The Leukemia & Lymphoma Society

The Mushett Family Foundation

Academy Friends

Anonymous

Shwachman-Diamond America

Shwachman-Diamond Syndrome Support Holland

Grant Support

The project described is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, and the National Heart, Lung, and Blood Institute. The content of this program is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institute, the National Heart, Lung, and Blood Institute or the National Institutes of Health.

In 1964, two teams of researchers independently reported the discovery of a new syndrome in humans. Characterized by insufficient digestive enzyme secretion from the pancreas, a shortage of neutrophil cells in the blood, and skeletal abnormalities such as short stature and distinctively cupped ribs, the condition became known as Shwachman-Diamond Syndrome or Shwachman-Bodian-Diamond Syndrome (SDS).

It appeared to have a simple genetic cause: unaffected "carriers" with one copy of the disease-inducing gene allele had a one-in-four chance of producing offspring with SDS. In genetic terms, it was an autosomal recessive condition. Almost 40 years later, molecular biologists linked SDS to a genetic locus on chromosome 7. Subsequent studies identified mutations in a single gene, dubbed SBDS, in most—but not all—SDS sufferers.

At the Sixth International Congress on Shwachman-Diamond Syndrome, held at the New York Academy of Sciences on June 28–30, researchers from around the world met to discuss the latest work on this puzzling condition. The meeting began with presentations about the major clinical features of SDS and the recent development of consensus guidelines for diagnosing it. Because not all SDS sufferers carry identifiable SBDS mutations, simple gene-based tests aren't sufficient. Instead, physicians must rely on a combination of genetic and clinical measures to identify cases.

The discussion then moved to the current management of SDS. Besides treating pancreatic insufficiency and neutropenia, physicians must also be prepared to address SDS patients' increased risk of acute myeloid leukemia (AML) and neurodevelopmental problems, which can include attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders.

After lunch, a panel discussion and workshop covered half a dozen international registries of SDS patients. Though the registries vary in scope and objectives, they have had to confront similar problems. Standardizing patient information from different physicians, designing robust databases, and defining inclusion criteria continue to be difficult challenges, but attendees reached broad agreement on several strategies for handling them.

The first day wrapped up with a session on model organisms for studying SDS. Because the SBDS gene is highly conserved, systems as diverse as fruit flies, mice, and zebrafish are helping uncover many aspects of the disease's biology.

The second day was all about research, beginning with an extensive session on the function of SBDS. The gene product is a protein that appears to be essential for normal ribosome maturation, a finding that only deepens the mystery of the human disease. Ribosomes translate messenger RNA into proteins, a process all cells must carry out, but human SDS primarily affects a few tissue types. Presenters in this session discussed several experimental models that help illuminate the disease's inner workings. A subsequent session included three talks about SBDS's specific function in hematopoietic, or blood cell, maturation and what that could mean for SDS patients who develop leukemia.

Day two concluded with a set of presentations about organ development and failure, especially the neural, pancreatic, and cardiac problems that commonly occur in SDS. The meeting picked up the same topic the next morning, but focused on the skeletal defects of the disease.

The final session included two presentations about promising diagnostic and therapeutic technologies. In both cases, researchers used relatively simple model organisms to characterize specific aspects of SDS, and then they moved into human cells to find molecules that could target those processes at the molecular level. Neither treatment is quite ready to go into patients yet, but the session provided ample reason for optimism about future treatment and prevention of this disease.

Though the primary focus of the meeting was on understanding SDS and helping people who suffer from it, scientists were quick to point out that findings in this disease are likely to be useful for a wide range of other problems.

As an example, William Cole, Chief of Paediatric Surgery at the University of Alberta, points to the field of skeletal health: "A lot of advances in understanding genes in bone health or skeletal health have actually come from the rare disorders; a lot of the big genetic studies of common conditions like osteoporosis and osteoarthritis have actually yielded relatively little new information."

Speakers:
Peter Durie, The Hospital For Sick Children, University of Toronto, Toronto, Canada
Taco Kuijpers, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands
Sanna Toiviainen-Salo, University Central Hospital, Helsinki, Finland
Akiko Shimamura, Fred Hutchinson Cancer Research Center
Monica Bessler, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine
Elizabeth N. Kerr, The Hospital for Sick Children, University of Toronto, Toronto, Canada

Participants in Workshop on International SDS Registries:
Akiko Shimamura, Fred Hutchinson Cancer Research Center
Blanche P. Alter, National Cancer Institute
Jean Donadieu, Trousseau Hospital, Paris, France
Yigal Dror, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Daniela Longoni, Clinica Pediatrica-Ospedale San Gerardo-Monza, Milan, Italy
Cornelia Zeidler, Hanover Medical School, Hanover, Germany
Johanna Rommens, The Hospital for Sick Children, University of Toronto
Shengjiang Tan, University of Cambridge, Cambridge, UK
Elayne Provost, Johns Hopkins University

Highlights

  • The SDS phenotype of pancreatic insufficiency, skeletal and marrow defects, and neurodevelopmental delays varies widely between patients.
  • New diagnostic techniques and consensus criteria should help define the patient population more clearly.
  • Patients with SDS often "fall through the cracks" of the healthcare system when they reach adulthood.
  • Patient registries are an imperfect, but essential tool for characterizing the SDS phenotype in more detail.
  • New animal models of SDS are helping researchers identify promising therapeutic targets in genetically tractable systems.

The clinical picture

Though the pathogenesis of Shwachman-Diamond Syndrome varies across individuals, pancreatic insufficiency is one highly consistent hallmark of it. "It does appear that the exocrine pancreas is affected in, I won't say all, but almost all individuals with Shwachman-Diamond Syndrome," said Peter Durie of the University of Toronto's Hospital for Sick Children. Accordingly, Durie opened the meeting with a review of the biology of the pancreas, which is divided into an endocrine portion responsible for blood sugar maintenance, and an exocrine side that secretes dozens of digestive enzymes into the bile duct.

Earlier studies revealed that the exocrine pancreas is extremely robust; even patients who have lost 95% of their pancreatic tissue secrete enough enzymes for digestion, but SDS patients often lack 99% of the organ. To identify these patients and track their progress over time, Durie advocates testing their serum for the enzymes trypsinogen and isoamylase, rather than doing more invasive endoscopic sampling and fat balance studies.

Taco Kuijpers, from Emma Children's Hospital and Academic Medical Center in Amsterdam, Netherlands, spoke next, presenting the recently agreed upon consensus guidelines for diagnosis and treatment of SDS. To highlight the difficulty of identifying this syndrome, Kuijpers also presented two cases that his team diagnosed with SDS, even though they did not display all of the traditional traits of the condition.

Novel imaging techniques might help diagnose some of those difficult cases, as Sanna Toiviainen-Salo of Helsinki University Hospital explained. After a brief overview of technologies such as computed tomography (CT) and magnetic resonance imaging (MRI), Toiviainen-Salo described studies that have revealed potentially useful diagnostic markers for SDS.

For example, while brain MRI scans appear normal in SDS patients, sophisticated computer-based analysis of the scans shows reduced gray and white matter. In another study, researchers found that patients with mutations in the SBDS gene display characteristic pancreatic pathology, with fat replacing a significant portion of the exocrine pancreas. A combination of imaging techniques could also help physicians track changes in skeletal, pancreatic, and other tissues over time, as many SDS patients manage to gain function in some organs as they grow up.

"New applications can provide completely new insights and may add to our understanding of this disease and its consequences in various body parts," Toiviainen-Salo concluded.

Lost in transition

In the conference's second session, Akiko Shimamura from the Fred Hutchinson Cancer Research Center described the major hematological problems that occur in SDS. Various cell types may be in short supply in these patients, leading to neutropenia, thrombocytopenia, or anemia, but the most feared complication of SDS is acute myeloid leukemia (AML). Standard chemotherapies often do not work well, and patients may require bone marrow transplants.

Monica Bessler of the Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine talked about managing the treatment of adults with SDS. As in many genetic conditions, patients tend to be diagnosed and treated most intensely in childhood, but as they become adults their medical care may fall through the cracks.

Patients with SDS present major challenges to adult physicians as they emerge from pediatric care.

As an example, Bessler described a 49-year-old SDS patient she sees, who has seven physicians and 20 pounds of medical records, and who has been hospitalized more than 100 times. The patient has a legal guardian involved in her medical decisions and is covered by both disability insurance and Medicare. For hematologists used to treating adults, "this is quite a challenge," said Bessler.

At the University of Pennsylvania, Bessler, in collaboration with Kim Overby, is now trying to address this problem by initiating dedicated pediatric-adult transition programs, including one for patients with acquired and inherited forms of Bone Marrow Failure. Such programs catch chronically ill patients as they "age out" of pediatric care and help get them get established in the adult care system.

Besides navigating the healthcare system, SDS patients often have trouble handling other aspects of daily life. Elizabeth Kerr from The Hospital for Sick Children at the University of Toronto explained that the disease commonly causes ADHD, oppositional-defiant disorder, autism spectrum disorders, and problems with higher-level intellectual function and social interactions.

These neurodevelopmental problems vary widely across the patient population, and also within a patient over time. Brain imaging studies suggest that SDS may lead to a decrease in white matter, neuronal wiring insulated by a myelin sheath, but Kerr cautions that these studies are viewing the end product of a complex pathway, and other mechanisms may be important earlier in development.

SDS registries

The meeting's third session featured a panel discussion and workshop on SDS disease registries. Because patients with this rare condition tend to be scattered widely, registries are essential for collecting and centralizing observational data about the disease.

Akiko Shimamura of the Fred Hutchinson Cancer Research Center started the session by describing the North American SDS Registry, which opened in December 2008. Seeking to understand the natural history of the disease and improve diagnosis and treatment, this registry initially set out to collect all of the clinical information on each of its participants. Limited time, money, and supplies have since forced the team to focus mainly on hematological complications.

Blanche Alter of the National Cancer Institute discussed her group's SDS and Bone Marrow Failure Registry, which covers all bone marrow failure syndromes. After presenting data on cancer rates in various populations within the registry, Alter offered some advice: "Patients must be classified properly, because if you have people in your registry ... who in retrospect don't have the right disease, it makes it very hard to interpret the data."

Jean Donadieu of Trousseau Hospital described his group's registry, which collects patient data from all over France to monitor leukemia risk in SDS and a few other disorders.

Yigal Dror of The Hospital for Sick Children at the University of Toronto talked about the Canadian Inherited Marrow Failure Registry, which aims to understand the clinical phenotype of SDS and other bone marrow failure syndromes.

Daniela Longoni from the Clinica Pediatrica-Ospedale San Gerardo-Monza in Italy summarized the data from another European registry. Longoni and her colleagues get medical records as well as bone marrow and blood samples from SDS patients seen in clinics scattered all over Italy.

Cornelia Zeidler of Hanover Medical School offered a perspective on the situation in Germany. Since 1994, her group has been collecting information on patients with rare disorders that lead to neutropenia, with a special focus on secondary events such as leukemia and osteoporosis.

In the workshop discussion, the group seemed to reach a consensus that while no registry design would ever be perfect, these efforts provide critical data for understanding the complex pathogenesis of SDS.

Building better models

The meeting's first day ended with a session on disease models of SDS. Johanna Rommens from the University of Toronto's Hospital for Sick Children described the SBDS gene, which is mutated in 90% of patients with SDS. Copying one of their patients' mutations into the mouse homolog of SBDS gave Rommens and her colleagues an animal model of the disease.

Knocking down SBDS expression in zebrafish prevents the exocrine pancreas from developing. (Image courtesy of Elayne Provost)

Meanwhile, Shengjiang Tan of the University of Cambridge mutated the gene in Drosophila melanogaster fruit flies to study its function and identify potential therapeutic targets for SDS. Elayne Provost of Johns Hopkins University performed similar experiments in the zebrafish, Danio rerio, and recapitulated many aspects of the human disease in this small, easily manipulated system.

Speakers:
Steven R. Ellis, University of Louisville
Arlen W. Johnson, The University of Texas at Austin
Alan J. Warren, University of Cambridge, Cambridge, UK
Johnson M. Liu, The Feinstein Institute for Medical Research
Umadas Mâitra, Albert Einstein College of Medicine of Yeshiva University
Stefano Biffo, San Raffaele Scientific Institute, Milan, Italy
Akiko Shimamura, Fred Hutchinson Cancer Research Center
Valentina André, Università di Milano-Bicocca, Milan, Italy

Highlights

  • The SBDS gene, mutated in most Shwachman-Diamond Syndrome patients, could have multiple functions in the cell—consequences of the gene's key role in ribosome maturation.
  • The major job of SBDS is to facilitate removal of eIF6 from the maturing 60S ribosomal subunit so it can assemble into a complete ribosome.
  • Inhibitors of eIF6 binding could become novel treatments for SDS.
  • Patients with SDS express very low levels of SBDS protein, but their bone marrow cells behave normally in cell culture systems.
  • SDS patients' marrow cells show transcriptional changes in 10 genes involved in embryogenesis.

The other translational research

The meeting's second day began with an extensive session on what many consider to be the key question in Shwachman-Diamond Syndrome: the function of the SBDS gene. Though SBDS encodes a relatively small protein involved in a specific step of ribosome maturation, the downstream effects of mutations in this gene are manifold.

In an overview of the session, Steven Ellis of the University of Louisville explained that "[there's] the potential that SBDS and its orthologs are multifunctional proteins, so we could have other potential functions outside of translation that fit into [SDS] phenotypes. So you can see the increasing complexity that we're working with here." Ellis then provided a description of his own work on this problem, which has shown that SBDS mutations in yeast cells cause downstream problems in mitochondrial ion channels, leading to metabolic defects.

The ribosome defect in SDS appears distinct from another bone marrow failure syndrome Diamond Blackfan anemia (DBA) as shown in the figure above highlighting yeast models for the two diseases. Cells with SDS-like mutations in their SBDS genes show defects in ribosome maturation, with 60S subunits piling up and a shortage of mature ribosomes. (Image courtesy of Steven Ellis)

Arlen Johnson of the University of Texas at Austin continued the discussion of yeast research but brought the focus back to the ribosome. He and his colleagues have found that SBDS works as a kind of unpackaging factor for the 60S ribosomal subunit. Johnson explained that the 60S subunit is manufactured in the cell's nucleolus and is then shipped to the cytoplasm with other proteins attached.

In order to use the ribosome, cytoplasmic factors such as SBDS must remove the "packaging" and then connect the 60S subunit to the 40S subunit. Mutations in SBDS can derail this crucial process and cause immature 60S subunits to pile up.

Remove before use

Alan J. Warren of the University of Cambridge talked about one of those packaging factors, called eukaryotic initiation factor 6, or eIF6. Warren and his colleagues discovered that mutations in the eIF6 gene can bypass loss of function mutations in the SBDS gene in yeast, and the group proposed a model in which SBDS cooperates with an enzyme called elongation factor-like 1 (EFL1) to directly trigger eIF6 release from maturing cytoplasmic 60S ribosomes. They have now validated this model in systems as diverse as slime mold, flies, mouse liver cells, and cells obtained directly from SDS patients.

In each case, specific defects in the SBDS protein block the release of eIF6 from the 60S ribosomal subunit, leaving an inadequate supply of mature ribosomes. Suppressor mutations in eIF6 can rescue the phenotypes in yeast, slime mold and flies, allowing the ribosomes to mature. Warren's team hopes to use that finding to search for drugs that modulate the affinity of the eIF6-60S subunit interaction to treat Shwachman-Diamond Syndrome.

Johnson M. Liu from the Feinstein Institute for Medical Research pursued the same story in human hematopoietic cells. His team has developed cultured cell models in which the expression of the SBDS gene has been knocked down either partially or almost completely. The partial knockdown causes a growth defect in a line of hematopoietic stem cells, reducing their ability to differentiate into myeloid progenitors, cells that differentiate into leukocytes. The near-complete knockdown, on the other hand, allows the researchers to look at more profound defects in ribosome maturation.

eIF6 must be removed from the 60S subunit for ribosomes to assemble properly. (Russell DW and Spremulli LL. Arch. Biochem. Biophys., 1980 and Valenzuela et al. J. Biol. Chem., 1982; Image courtesy of Alan Warren)

Umadas Mâitra from Albert Einstein College of Medicine of Yeshiva University also studies ribosome maturation defects. After a brief review of the biology of ribosomes particularly with regard to the function of eIF6 in 60S ribosome biogenesis and assembly in the nucleolus, Mâitra explained recent results showing that eIF6 is phosphorylated on two adjacent serine residues that are conserved across all nucleated species. Clearly, phosphorylation is somehow important for eIF6 function since failure to phosphorylate eIF6 causes loss of cell growth and viability at least of yeast cells, but how?

These researchers hypothesized that eIF6 phosphorylation and its dephosphorylation might be required for shuttling between the nucleus and cytoplasm. Seventy-five percent of the eIF6 in a typical mammalian cell is in the cytoplasm, so there must be some mechanism for sending it back to the nucleolus for its continued function in 60S ribosome biogenesis and assembly. Mutating the eIF6 phosphorylation sites shuts off nuclear export and leaves a pool of the protein stuck in the nucleus. Based on their results, Mâitra proposes a model in which a specific kinase phosphorylates eIF6 to tag it for export to the cytoplasm along with its attached 60S ribosomal subunits. Once in the cytoplasm, a specific phosphatase dephosphorylates eIF6 after it detaches from the maturing ribosome, sending the packaging factor back into the nucleus for re-use.

Moving the discussion toward practical applications, Stefano Biffo from the San Raffaele Scientific Institute presented new results and a novel screening system for identifying compounds that inhibit eIF6 association with ribosomes. Biffo's team has found that eIF6 defects can have profound and puzzling downstream effects in animal models. For example, mice with one copy of their EIF6 genes deleted show a reduction in cytoplasmic eIF6 but not nuclear eIF6 levels. The heterozygous mice also have lower body weights and less fat because of a decrease in the proliferation of the stem cell precursor of adipocytes, or fat cells.

In separate work, the investigators have developed a high-throughput-screening–adaptable system that uses immobilized ribosomes to look for compounds that alter eIF6 binding. "I think that by this method we can probably try to screen molecules which are acting as agonists and antagonists of eIF6 which interfere with 60S binding, and maybe they can even be useful in treatment of Shwachman[-Diamond Syndrome]," said Biffo.

Patients, please

Akiko Shimamura from the Fred Hutchinson Cancer Research Center spoke next, presenting unpublished results on the function of SBDS in multiple cellular processes. Patients with SDS don't express much SBDS protein, but Shimamura pointed out that all of the patients tested to date produce at least some of it—there are no documented cases of homozygous null mutations in humans. That's consistent with mouse models, in which complete deletion of both copies of the SBDS gene is lethal. Instead, SDS patients appear to be hypomorphs, expressing low levels of the SBDS protein.

Valentina André of the Università di Milano–Bicocca wrapped up the session by presenting her work on bone marrow dysfunction in SDS. She and her colleagues are working directly with mesenchymal stem cells from the bone marrow of patients with mutations in the SBDS gene. Initial tests showed that these cells grow and differentiate normally in several tissue culture tests and that they are even able to protect neutrophils from apoptosis; to a first approximation, they are as functional as mesenchymal stem cells from healthy controls.

Next, the scientists profiled gene expression patterns in patient and control marrow cells, and found ten genes that are differentially expressed in the SDS patient marrow. All of the genes are involved in embryogenesis, suggesting that they could illuminate the disease's characteristic developmental abnormalities. While still far from clinical application, the work—and the other presentations in the session—showed the remarkable progress the field has made in understanding SBDS's functions.

Speakers:
Paul S. Frenette, Albert Einstein College of Medicine of Yeshiva University
Jeffrey M. Lipton, Steven and Alexandra Cohen Children's Medical Center of New York
David T. Scadden, Massachusetts General Hospital, Harvard Medical School
Yigal Dror, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Russell Schachar, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Sabrina C. Desbordes, Center for Genomic Regulation
Steven D. Leach, Johns Hopkins University School of Medicine
Marina E. Tourlakis, University of Toronto, The Hospital for Sick Children, Toronto, Canada
Ibrahim Domian, Harvard Medical School, Massachusetts General Hospital

Highlights

  • A special niche in the bone marrow appears to be responsible for maintaining and directing hematopoietic stem cell development.
  • An increase in programmed cell death may be responsible for the neutropenia seen in SDS patients.
  • Attention-deficit hyperactivity disorder is a common but undertreated complication of SDS.
  • Stem cell models can illuminate some of the neurodevelopmental defects caused by SBDS gene mutations.
  • SDS patients have some heart abnormalities, and a new tissue engineering system could help discover new therapies for them.

Tracing the bloodlines

After learning about the general functions of the SBDS protein, attendees heard several talks about how defects in SBDS can contribute to hematopoietic dysfunction, or errors in blood cell development.

Paul Frenette of Albert Einstein College of Medicine began the session by recounting his team's hunt for the elusive hematopoietic stem cell niche. Proposed decades ago, the niche is a hypothetical compartment inside the bone marrow where stem cells mature into specific hematopoietic lineages. In the hematopoietic niche, the microenvironment maintains stem cells in their undifferentiated state, and helps them decide when to proliferate and differentiate. "The concept was nice, but the tough part has been to prove it," said Frenette.

After finding circadian fluctuations in the levels of circulating hematopoietic stem cells, Frenette and his colleagues tracked the signals for this phenomenon. Eventually, they identified a complex interplay between the nervous system and specific compartments of bone marrow cells expressing the gene NES, called nestin. Isolating and culturing these nestin-positive cells, the researchers were able to develop self-renewing cellular spheres that could differentiate into the major hematopoietic lineages. The results suggest that these cells could be connected to the hematopoietic niche.

Delivering the 22nd Annual Jason Bennette Memorial Lecture, David Scadden from Massachusetts General Hospital and Harvard Medical School talked about his work on bone marrow dysfunction and leukemia. Initially, Scadden and his colleagues found that disrupting gene expression in mouse osteoblast progenitor cells causes only mild bone abnormalities but leads to profound defects in blood cells, apparently by damaging the bone marrow microenvironment in which hematopoietic cells develop.

Mesenchymal stem cells give rise to adipocytes, chondrocytes, and osteocytes.

The researchers then did a sophisticated series of labeling and disruption experiments to trace the osteoprogenitor lineage, eventually identifying a marker protein called Mx1 that labels a long-lived mesenchymal stem cell population. The cells partially overlap with Frenette's Nestin-positive cell population, suggesting that the two teams are converging on a common stem cell compartment within the bone marrow.

Yigal Dror of the Hospital for Sick Children at the University of Toronto finished the session with a discussion of hematopoiesis and leukemia in SDS patients. All SDS patients have at least some hematopoietic problems, with neutropenia being universal and other defects, such as anemia and thrombocytopenia, being relatively common. SBDS protein expression increases early in hematopoiesis.

Dror and his colleagues found that SBDS-deficient blood progenitor cultures grow slowly compared to healthy controls, and introducing wild-type SBDS into these cells rescues them. The problem seems to derive from increased apoptosis, or programmed cell death, in the cultures of mutant cells, possibly as a result of an increase in reactive oxygen species.

Brains, guts, and heart

Russell Schachar, also from Toronto's Hospital for Sick Children, opened the meeting's seventh session, which focused on organ development and failure in SDS. Schachar works on attention deficit hyperactivity disorder (ADHD), a condition that affects about 4% of the general population. Neurodevelopmental disorders such as SDS carry a significantly increased risk of ADHD. Unfortunately, physicians often fail to diagnose or treat ADHD in neurodevelopmentally disabled patients.

Schachar argued that in order to improve ADHD treatment in SDS patients, researchers should focus on specific clinical trials to bolster the evidence of the efficacy of stimulants and nondrug interventions in these patients. "There is clearly a need for further evidence pertaining to the clinical presentation of kids with SDS in terms of their learning and their behavior," said Schachar.

While clinical studies are clearly necessary, laboratory research can also illuminate the neurodevelopmental defects of SDS. For example, Sabrina Desbordes from the Center for Genomic Regulation discussed her work using human embryonic stem cells (hESCs) to study neuronal development.

Because they can differentiate into neural stem cells, hESCs can recapitulate many aspects of brain development in a petri dish. Inhibiting the SBDS gene with RNA interference in these cells causes an increase in cell death and impaired cell division. Desbordes and her colleagues have also adapted hESCs for use in a high-throughput screening campaign, which allows them to test thousands of compounds for potentially relevant neurodevelopmental effects.

Steven Leach, from the Johns Hopkins University School of Medicine, talked about two models for studying pancreatic development, a process that clearly goes awry in SDS. In mice, Leach and his colleagues have focused on the effects of the transcriptional regulators PDX1 and PTF1. "These can be thought of as the two master regulatory genes of pancreas development," said Leach. All pancreatic cell types arise from a progenitor cell that expresses both genes.

The same genes regulate pancreatic development in the zebrafish, where the researchers discovered that PDX1 establishes a general zone in which the pancreas can form, and PTF1 operates within that zone to direct the organ's construction.

Marina Tourlakis from the Hospital for Sick Children and University of Toronto described two mouse models with SBDS mutations targeted to the pancreas. One strain models the disease condition with a missense mutation and a null, and the other strain carries two null mutations and hence yields no SBDS function. The targeted approach means these modifications are only present in pancreatic cells, thereby avoiding the lethality of a global SBDS knock-out. These systems mimic many aspects of human SDS, and should help Tourlakis and her colleagues determine why SBDS mutations preferentially affect certain organs.

Stem cells on an engineered substrate grow into functional heart tissue, which can be induced to beat.

Ibrahim Domian from Harvard Medical School and Massachusetts General Hospital turned the discussion to an organ that gets less attention in SDS: the heart. A wide range of tests on patients' hearts show a small reduction in cardiac contractility, which only becomes significant when the patients are tested under stress.

To understand how the heart develops in healthy and diseased individuals, Domian's team created a mouse that expresses red and green fluorescent proteins from promoters specific for different heart development genes. The color-coded hearts can help trace where problems in the adult animal arose. Isolating embryonic stem cells from these mice, the scientists then collaborated with a tissue engineering lab to grow functional myocardial tissue, which could be used to test any treatments purported to restore full contractility.

Domian and his colleagues are also using a high-throughput approach to identify compounds that will keep the cultured heart cells replicating. So far, they have found one hit that induces a fifty-fold expansion in the cell population. That compound and the wide range of laboratory models featured throughout the day's sessions point to a bright future for studies on novel SDS therapies.

Speakers:
Outi Mäkitie, Children's Hospital, University of Helsinki, Helsinki, Finland
Gerard Karsenty, Columbia University College of Physicians and Surgeons
William G. Cole, University of Alberta, Edmonton, Canada
M. William Lensch, Children's Hospital Boston, Harvard Medical School
Paul de Figueiredo, Texas A&M University and Texas A&M Health Science Center

Highlights

  • Patients with SDS display a wide variety of defects in skeletal development.
  • Leptin and serotonin coordinate bone growth with energy metabolism.
  • Rare conditions such as SDS have been highly informative for biomedical research.
  • The yeast S. cerevisiae provides a good model for screening drugs to treat SDS.

SDS and the skeletal system

The session on organ development and failure continued into the conference's final day. Outi Mäkitie from the Hospital for Children and Adolescents at the University of Helsinki began with an overview of the skeletal phenotype of Shwachman-Diamond Syndrome.

The condition affects several levels of skeletal development, including longitudinal bone growth, modeling, and remodeling of bones. As a result, patients tend to have short stature, failure to thrive, variable growth failures during childhood, and low-normal adult height. Their ribs commonly have cupped ends, which can be so severely deformed that they cause asphyxiation. SDS patients also have low bone mass, so Mäkitie and her colleagues analyzed bone biopsies from several patients and found significant low-turnover osteoporosis. In this condition, bone deteriorates through inadequate bone formation rather than through overactive breakdown by osteoclasts.

Her findings imply that physicians should prescribe calcium and vitamin D supplements for their patients but avoid osteoporosis drugs that target osteoclasts, as osteoporosis in SDS appears not to be a result of increased osteoclast activity.

Gerard Karsenty from the Columbia University College of Physicians and Surgeons expanded the bone discussion to encompass the brain and gut. As Karsenty explained, bone growth, energy metabolism, and reproduction all seem to be coordinated in animals, and this coordination must be ancient. "Bone [is] the only organ that we have that contains a cell type, the osteoclast, whose only function is to destroy the host tissue," said Karsenty, adding that "the hormone responsible for that, at least the main one, would appear during evolution with bone."

Leptin acts on the brain to connect energy metabolism to bone growth.

Leptin seems to be a good candidate. It appeared at the right point in evolution, and mice lacking leptin have unusually high bone density. Giving the animals leptin corrects their bone phenotype. Through an elegant series of mouse genetic experiments, Karsenty and his colleagues determined that leptin, commonly associated with energy metabolism, also signals through serotonin in the brain to regulate bone density. An experimental serotonin synthesis inhibitor is now in phase 1 clinical trials as a potential treatment for osteoporosis. The drug acts specifically on bone formation, so it might also prove useful in treating some of the skeletal defects in SDS patients.

William Cole from the University of Alberta finished the session on organ development with an overview of skeletal dysplasias. This family of disorders includes 456 conditions, which are subdivided into 40 groups by their molecular, biochemical, and clinical features. In 316 of these conditions, researchers have identified mutations in specific genes. SDS falls into the category of metaphyseal dysplasias, which especially affect the metaphyseal plates that drive bone growth in childhood.

Reviewing the literature on SDS and another condition, called early-onset metaphyseal dysplasia, type Schmid, Cole pointed out that these rare conditions have provided enormous insight on normal bone biology. "In the common conditions, the genes that appear to be involved probably have low dose effects, whereas in these particular conditions the mutations have a high dose effect, so they're sort of easier to identify," said Cole.

In Schmid type dysplasia, for example, patients' mutations pointed to a defect in collagen, in which one defective copy of the gene can reduce the ability of wild-type collagen to polymerize, leading to failures in bone formation. The findings helped show the importance of collagen self-polymerization.

Brewing up treatments

The final session of the Congress featured two talks about novel diagnostic and therapeutic approaches for SDS. M. William Lensch from Children's Hospital Boston and Harvard Medical School discussed recent, unpublished data from his work on human pluripotent stem cells. Lensch and his colleagues use these cells, which can differentiate into a variety of tissue types, to model specific diseases in vitro. For SDS, they knocked down expression of the SBDS gene in embryonic stem cells and also studied induced pluripotent stem cells from SDS patients. When the cells differentiate into blood and pancreatic tissue they reveal several novel aspects of SDS biology.

A high-throughput screen of a yeast model of SDS yielded several potential drug leads.

Paul de Figueiredo from Texas A&M University discussed a very different model for clinical research: the brewer's yeast Saccharomyces cerevisiae. While yeast's rapid reproduction and straightforward genetics make it a popular tool for basic cell biology studies, Figueiredo's team decided to use it as a drug-screening platform.

The SBDS gene is highly conserved, so drugs that target the yeast version of it could be useful leads for human therapies. Accordingly, the researchers tested two large libraries of compounds to find those that increased the growth rate of yeast cells lacking SDO1, the yeast homolog of human SBDS. After several additional tests, the field narrowed to 25 highly active compounds in seven distinct structural categories. Testing one of the best hits, Trichostatin A, in a human cell model confirmed that the drug partially reverses defects in SBDS in these cells as well.

Interestingly, Trichostatin A inhibits histone deacetylase rather than acting directly on SBDS. De Figueiredo hypothesizes that SBDS regulates histone acetylation patterns, and inhibiting histone deacetylase can compensate for some defects in this activity.

As the meeting finished, attendees were left with a clear view of the two-way exchange that characterizes research on rare diseases: the patients' own experiences inform novel avenues of research, which in turn produce new approaches to treatment.