Mutations in SBDS are associated with Shwachman–Diamond syndrome

GRB Boocock, JA Morrison, M Popovic, N Richards… - Nature …, 2003 - nature.com
GRB Boocock, JA Morrison, M Popovic, N Richards, L Ellis, PR Durie, JM Rommens
Nature genetics, 2003nature.com
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 1, 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 disease 5, 6. We report that SBDS has a 1.6-kb
transcript and encodes a predicted protein of 250 amino acids. A pseudogene copy …
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 1, 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 disease 5, 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 genes 7, 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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