title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
abstract: Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction and skeletal abnormalities. 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 disease. 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 genes, 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.
authors.affiliation: 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.
authors.forename: Graeme R B
authors.initials: GR
authors.lastname: Boocock
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Morrison
authors.forename: Maja
authors.initials: M
authors.lastname: Popovic
authors.forename: Nicole
authors.initials: N
authors.lastname: Richards
authors.forename: Lynda
authors.initials: L
authors.lastname: Ellis
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics*; D005260:Female; D005785:Gene Conversion; D020869:Gene Expression Profiling; D006402:Hematologic Diseases / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009139:Musculoskeletal Abnormalities / Q000235:genetics*; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D011544:Pseudogenes / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome
chemical_list: D011506:Proteins; D012333:RNA, Messenger; C470521:SBDS protein, human