Letter | Published:

Mutations in SBDS are associated with Shwachman–Diamond syndrome

Nature Genetics volume 33, pages 97101 (2003) | Download Citation


This article has been updated


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Change history

  • 04 March 2003

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



  1. 1.

    , , & The syndrome of pancreatic insufficiency and bone marrow dysfunction. J. Pediatr. 65, 645–663 (1964).

  2. 2.

    , & Congenital hypoplasia of the exocrine pancreas. Acta Pædiat. 53, 282–293 (1964).

  3. 3.

    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).

  4. 4.

    et al. Segregation analysis in Shwachman–Diamond syndrome: evidence for recessive inheritance. Am. J. Hum. Genet. 66, 1413–1416 (2000).

  5. 5.

    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).

  6. 6.

    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).

  7. 7.

    , & 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).

  8. 8.

    , & 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).

  9. 9.

    & Molecular basis of hereditary pancreatitis. Eur. J. Hum. Genet. 8, 473–479 (2000).

  10. 10.

    , , , & 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).

  11. 11.

    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).

  12. 12.

    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).

  13. 13.

    et al. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat. Genet. 11, 335–337 (1995).

  14. 14.

    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).

  15. 15.

    Molecular pathology of 21-hydroxylase deficiency. J. Inherit. Metab. Dis. 17, 430–441 (1994).

  16. 16.

    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).

  17. 17.

    et al. The Pfam protein families database. Nucleic Acids Res. 30, 276–280 (2002).

  18. 18.

    et al. Global analysis of protein activities using proteome chips. Science 293, 2101–2105 (2001).

  19. 19.

    et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901–906 (1999).

  20. 20.

    et al. Large-scale prediction of Saccharomyces cerevisiae gene function using overlapping transcriptional clusters. Nat. Genet. 31, 255–265 (2002).

  21. 21.

    et al. Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman–Diamond syndrome. J. Pediatr. 141, 259–265 (2002).

  22. 22.

    , & A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215 (1988).

  23. 23.

    , , & Isolation of RNA using guanidinium salts. Meth. Enzymol. 152, 219–234 (1987).

  24. 24.

    et al. GenBank. Nucleic Acids Res. 30, 17–20 (2002).

  25. 25.

    et al. The Ensembl genome database. Nucleic Acids Res. 30, 38–41 (2002).

  26. 26.

    et al. PipMaker—a web server for aligning two genomic DNA sequences. Genome Res. 10, 577–586 (2000).

  27. 27.

    & 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).

  28. 28.

    & Molecular Cloning (Cold Spring Harbor Laboratory Press, New York, 2001).

  29. 29.

    , , , & The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 24, 4876–4882 (1997).

Download references


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


  1. Program in Genetics and Genomic Biology, Room 11-109A, Elm Wing Annex, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, 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, Ontario M5S 1A8, 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


  1. Search for Graeme R.B. Boocock in:

  2. Search for Jodi A. Morrison in:

  3. Search for Maja Popovic in:

  4. Search for Nicole Richards in:

  5. Search for Lynda Ellis in:

  6. Search for Peter R. Durie in:

  7. Search for Johanna M. Rommens in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Johanna M. Rommens.

Supplementary information

PDF files

  1. 1.

    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.

About this article

Publication history