Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome

Abstract

Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insuffi-ciency, bone marrow dysfunction, and metaphyseal chondrodysplasia. Recent studies show that mutations of SBDS, a gene of unknown function, are present in the majority of patients with SDS. In the present study, we show that most, but not all, patients classified based on rigorous clinical criteria as having SDS had compound heterozygous mutations of SBDS. Full-length SBDS protein was not detected in leukocytes of SDS patients with the most common SBDS mutations, consistent with a loss-of-function mechanism. In contrast, SBDS protein was expressed at normal levels in SDS patients without SBDS mutations. These data confirm the absence of SBDS mutations in this subgroup of patients and suggest that SDS is a genetically heterogeneous disorder. The presence (or absence) of SBDS mutations may define subgroups of patients with SDS who share distinct clinical features or natural history. (Blood. 2004;104: 3588-3590) Introduction Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and metaphyseal chondrodyspla-sia. 1-5 SDS is the second most common cause of congenital exocrine pancreatic insufficiency, after cystic fibrosis. Bone marrow dysfunction is present in nearly all patients with SDS. 3-6 In the largest published series (88 patients), chronic or intermittent neutropenia was present in 97%. 5 Anemia and thrombocyto-penia were present in more than a third of patients. Patients with SDS have a marked propensity to develop myelodysplasia or acute myeloid leukemia. 6-8 SDS is inherited in an autosomal recessive fashion. 9 Recently , Boocock et al 10 reported that compound heterozygous mutations of the SBDS (Shwachman-Bodian-Diamond syndrome) gene on chromosome 7 were present in the majority of patients with SDS. Most of these mutations resulted from gene conversion with a neighboring pseudogene (SBDSP). Similar data were reported in a smaller series of patients of Japanese ancestry. 11 Most of the SBDS mutations are predicted to truncate a substantial portion of the SBDS protein, suggesting that they act in a loss-of-function manner. Herein, we show that most, but not all, patients classified prospectively based on clinical criteria as having probable SDS had SBDS gene mutations. Moreover, a strong correlation between SBDS genotype and expression of full-length SBDS protein was observed. Study design Human subjects There were 33 families who attended the Second International Conference on Shwachman-Diamond Syndrome in St Louis in 1999 and who were invited to participate in a study to elucidate the genetic basis of SDS. After obtaining informed consent, a thorough history, physical examination, review of medical records, and selected laboratory testing were performed. In addition, genomic DNA was extracted from peripheral blood leukocytes using standard protocols. The diagnosis of SDS was based on the presence of the followin...

The role of telomere biology in bone marrow failure and other disorders

“…Decreased serum trypsinogen and isoamylase are useful diagnostic tests but the latter is not reliable for children less than three years of age (Ip et al 2002). At least 90% of patients with SDS have been found to have mutations in the SBDS gene (Woloszynek et al 2004). The role of SBDS, a member of a highly conserved gene family that functions in RNA metabolism, is currently being elucidated.…”

Some cases of common variable immunodeficiency may be due to a mutation in the SBDS gene of Shwachman–Diamond syndrome

“…It has an extremely heterogeneous clinical presentation, as does CVID, but 90% of patients meeting clinical criteria have mutations in the Shwachman-BodianDiamond syndrome gene (SBDS) (see Table 4 for summary of genetic mutations identified in CVID and SDS). The SBDS gene located on chromosome 7q11 is highly conserved in archaea, plants and eukaryotes [3,16]. The protein is predicted to have 250 amino acids and gene conversion during meiosis with its neighbouring pseudogene, SBDSP (the duplicon of SBDS gene located 5·8Mb distally with nucleotide sequence homology of 97%), which results in the [17] and studies in yeast homologues suggest a role in ribosomal RNA processing [18,19].…”

“…Hepatomegaly, elevated liver enzymes and malabsorption due to pancreatic insufficiency seen in SDS may improve over time in about half the patients [2,26]. Random faecal elastase determination can provide sufficient information of pancreatic exocrine function [27] but, as adult patients with SDS may be pancreatic sufficient, the clinical [3,16] criterion of exocrine pancreatic insufficiency does not appear to be essential for the diagnosis of SDS. Pancreatic insufficiency may be ameliorated by enzyme supplementation.…”

Identification of a novel AluSx-mediated deletion of exon 3 in the SBDS gene in a patient with Shwachman–Diamond syndrome

“…The majority of mutations described in the SBDS gene are said to represent gene conversion events due to recombination with its pseudogene SBDSP, with which it shares 97% identity [7,[10][11][12][13]. Many have been found to occur within a 240 bp region around exon 2, which harbors the most frequent mutations c.183_184TA>CT and c.258 + 2T>C. These are often seen to be associated with the polymorphic variants c.141C>T and/or c.201A>G, presumably as a result of the size of the DNA fragments involved in the rearrangements [7,9,10,12,13].…”

“…Many have been found to occur within a 240 bp region around exon 2, which harbors the most frequent mutations c.183_184TA>CT and c.258 + 2T>C. These are often seen to be associated with the polymorphic variants c.141C>T and/or c.201A>G, presumably as a result of the size of the DNA fragments involved in the rearrangements [7,9,10,12,13]. However, mutations may occur throughout the gene, as evidenced by the 22 variants documented to date.…”