Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in SBDS are associated with Shwachman–Diamond syndrome

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Integrated map of the interval associated with SDS.
Figure 2: Mutations in SBDS cause SDS.
Figure 3: Expression analyses of SBDS and SBDSP.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Change history

  • 04 March 2003

    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 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Johanna M. Rommens.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Web Fig. A

NOTE: In the Supplementary Information for this paper originally published online, Web Figure A did not include a legend. We have since added the legend.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1062

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing