Mutations in SBDS are associated with Shwachman–Diamond syndrome (original) (raw)

Nature Genetics volume 33, pages 97–101 (2003)Cite this article

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Abstract

Shwachman–Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction and skeletal abnormalities1,2,3,4. Here, we report identification of disease-associated mutations in an uncharacterized gene, SBDS, in the interval of 1.9 cM at 7q11 previously shown to be associated with the disease5,6. We report that SBDS has a 1.6-kb transcript and encodes a predicted protein of 250 amino acids. A pseudogene copy (SBDSP) with 97% nucleotide sequence identity resides in a locally duplicated genomic segment of 305 kb. We found recurring mutations resulting from gene conversion in 89% of unrelated individuals with SDS (141 of 158), with 60% (95 of 158) carrying two converted alleles. Converted segments consistently included at least one of two pseudogene-like sequence changes that result in protein truncation. SDBS is a member of a highly conserved protein family of unknown function with putative orthologs in diverse species including archaea and eukaryotes. Archaeal orthologs are located within highly conserved operons that include homologs of RNA-processing genes7, suggesting that SDS may be caused by a deficiency in an aspect of RNA metabolism that is essential for development of the exocrine pancreas, hematopoiesis and chrondrogenesis.

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Added the revised supplementary figure A, which contained a figure legend

References

  1. Shwachman, H., Diamond, L.K., Oski, F.A. & Khaw, K.T. The syndrome of pancreatic insufficiency and bone marrow dysfunction. J. Pediatr. 65, 645–663 (1964).
    Article CAS Google Scholar
  2. Bodian, M., Sheldon, W. & Lightwood, R. Congenital hypoplasia of the exocrine pancreas. Acta Pædiat. 53, 282–293 (1964).
    Article CAS Google Scholar
  3. Ginzberg, H. et al. Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. J. Pediatr. 135, 81–88 (1999).
    Article CAS Google Scholar
  4. Ginzberg, H. et al. Segregation analysis in Shwachman–Diamond syndrome: evidence for recessive inheritance. Am. J. Hum. Genet. 66, 1413–1416 (2000).
    Article CAS Google Scholar
  5. Goobie, S. et al. Shwachman–Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am. J. Hum. Genet. 68, 1048–1054 (2001).
    Article CAS Google Scholar
  6. Popovic, M. et al. Fine mapping of the locus for Shwachman–Diamond syndrome at 7q11, identification of shared disease haplotypes, and exclusion of TPST1 as a candidate gene. Eur. J. Hum. Genet. 10, 250–258 (2002).
    Article CAS Google Scholar
  7. Koonin, E.V., Wolf, Y.I. & Aravind, L. Prediction of the archaeal exosome and its connections with the proteasome and the translation and transcription machineries by a comparative-genomic approach. Genome Res. 11, 240–252 (2001).
    Article CAS Google Scholar
  8. Antonarakis, S.E., Krawczak, M. & Cooper, D.N. in The Metabolic and Molecular Basis of Inherited Disease (eds. Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 343–377 (McGraw-Hill, New York, 2001).
    Google Scholar
  9. Chen, J.M. & Ferec, C. Molecular basis of hereditary pancreatitis. Eur. J. Hum. Genet. 8, 473–479 (2000).
    Article CAS Google Scholar
  10. Chen, J.M., Raguenes, O., Ferec, C., Deprez, P.H. & Verellen-Dumoulin, C.A. CGC→CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis. J. Med. Genet. 37, E36 (2000).
    Article CAS Google Scholar
  11. Cai, L. et al. A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum. J. Mol. Med. 79, 536–546 (2001).
    Article CAS Google Scholar
  12. Bunge, S. et al. Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II. Eur. J. Hum. Genet. 6, 492–500 (1998).
    Article CAS Google Scholar
  13. Bussaglia, E. et al. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat. Genet. 11, 335–337 (1995).
    Article CAS Google Scholar
  14. Hahnen, E. et al. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Am. J. Hum. Genet. 59, 1057–1065 (1996).
    CAS PubMed PubMed Central Google Scholar
  15. Strachan, T. Molecular pathology of 21-hydroxylase deficiency. J. Inherit. Metab. Dis. 17, 430–441 (1994).
    Article CAS Google Scholar
  16. Roesler, J. et al. Recombination events between the p47-phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease. Blood 15, 2150–2156 (2000).
    Google Scholar
  17. Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 30, 276–280 (2002).
    Article CAS Google Scholar
  18. Zhu, H. et al. Global analysis of protein activities using proteome chips. Science 293, 2101–2105 (2001).
    Article CAS Google Scholar
  19. Winzeler, E.A. et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901–906 (1999).
    Article CAS Google Scholar
  20. Wu, L.F. et al. Large-scale prediction of Saccharomyces cerevisiae gene function using overlapping transcriptional clusters. Nat. Genet. 31, 255–265 (2002).
    Article CAS Google Scholar
  21. Ip, W.F. et al. Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman–Diamond syndrome. J. Pediatr. 141, 259–265 (2002).
    Article CAS Google Scholar
  22. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215 (1988).
    Article CAS Google Scholar
  23. MacDonald, R.J., Smith, G.H., Przybyla, A.E. & Chirgwin, J.M. Isolation of RNA using guanidinium salts. Meth. Enzymol. 152, 219–234 (1987).
    Article CAS Google Scholar
  24. Benson, D.A. et al. GenBank. Nucleic Acids Res. 30, 17–20 (2002).
    Article CAS Google Scholar
  25. Hubbard, T. et al. The Ensembl genome database. Nucleic Acids Res. 30, 38–41 (2002).
    Article CAS Google Scholar
  26. Schwartz, S. et al. PipMaker—a web server for aligning two genomic DNA sequences. Genome Res. 10, 577–586 (2000).
    Article CAS Google Scholar
  27. Rozen, S. & Skaletsky, H.J. Primer3 on the WWW for general users and for biologist programmers. In Bioinformatics Methods and Protocols: Methods in Molecular Biology (eds. Krawetz, S. & Misener, S.) (Humana, Totowa, New Jersey, 2000).
    Google Scholar
  28. Sambrook, J. & Russell, D.W. Molecular Cloning (Cold Spring Harbor Laboratory Press, New York, 2001).
    Google Scholar
  29. Thompson, J.D., Gibson, T.J., Plewniak, F., Jeanmougin, F. & Higgins, D.G. The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 24, 4876–4882 (1997).
    Article Google Scholar

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Acknowledgements

We thank the individuals with SDS, their families and their physicians for their cooperation; M. Corey, N. Ehtesham, D. Ellenor, H. Ginzberg, S.L. Goobie, K. Hagerman, W. Ip, K. Kwon, A. Owaisi and M. Rozenberg for their contributions; and the Canadian Institutes of Health Research Genome Resource Facility and the Sequencing Facility of The Center for Applied Genomics for technical support. We acknowledge support from Shwachman–Diamond Syndrome Canada, Shwachman–Diamond Support of Great Britain, The Harrison Wright Appeal, Shwachman Syndrome Support of Australia, Shwachman–Diamond Syndrome International, Pediatric Consultants, and the Canadian Institutes of Health Research. J.M.R. is a member of the Centers of Excellence/Canadian Genetic Diseases Network. M.P. and G.R.B.B. received Ontario Graduate Scholarships and joint training awards from the Canadian Genetic Diseases Network and The Hospital for Sick Children. G.R.B.B. is also the recipient of a Canadian Institutes of Health Research doctoral research award.

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Authors and Affiliations

  1. Program in Genetics and Genomic Biology, Room 11-109A, Elm Wing Annex, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada
    Graeme R.B. Boocock, Jodi A. Morrison, Maja Popovic, Nicole Richards & Johanna M. Rommens
  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, M5S 1A8, Ontario, Canada
    Graeme R.B. Boocock, Maja Popovic & Johanna M. Rommens
  3. Program in Integrative Biology, Research Institute, and Division of Gastroenterology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
    Lynda Ellis & Peter R. Durie
  4. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
    Lynda Ellis & Peter R. Durie

Authors

  1. Graeme R.B. Boocock
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  2. Jodi A. Morrison
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  3. Maja Popovic
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  4. Nicole Richards
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  5. Lynda Ellis
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  6. Peter R. Durie
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  7. Johanna M. Rommens
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Correspondence toJohanna M. Rommens.

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Boocock, G., Morrison, J., Popovic, M. et al. Mutations in SBDS are associated with Shwachman–Diamond syndrome.Nat Genet 33, 97–101 (2003). https://doi.org/10.1038/ng1062

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