Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0272170 (SDS)
 50,377 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mutations in SBDS are associated with Shwachman-Diamond syndrome. 1249 57

Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction and metaphyseal chondrodysplasia. SDS is caused by mutations in SBDS, an uncharacterized gene. A previous study in SDS patients largely of European ancestry found that most SBDS mutations occurred within a approximately 240-bp region of exon 2 and resulted from gene conversion due to recombination with a pseudogene, SBDSP. It is unknown, however, whether these findings are applicable to other ethnic groups. To address this question, we examined SBDS mutations in six Japanese families with SDS by direct sequencing. We identified compound heterozygous mutations in four families: two were recurrent (96-97insA, 258+2T>C), and three were novel [292-295delAAAG, (183-184TA>CT +201A>G), (141C>T+183-184TA>CT+201A>G)] mutations. Most of these mutations also appear to result from gene conversion, but the conversion events occurred at various sites between intron 1 and exon 3. Thus, gene conversion mutations in SBDS are common to different ethnic groups, but they are not confined to a limited region of the gene.
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PMID:Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome. 1474 21

Pancreatic exocrine and bone marrow dysfunctions are considered to be universal features of Shwachman-Diamond syndrome (SDS) whereas the associated skeletal dysplasia is variable and not consistently observed. The genetic defect in SDS has recently been identified; causative mutations have been shown in the SBDS gene. The aims of this study were to characterize the nature, frequency, and age-related changes of radiographic skeletal abnormalities in patients with SBDS mutations and to assess genotype-phenotype correlation. Fifteen patients (mean age 9.7 years) with a clinical diagnosis of SDS and documented SBDS gene mutations were included. Review of their skeletal radiographs showed abnormalities in all patients. The skeletal changes were variable, even in patients with identical genotypes. The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia. There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age. The results suggest that the characteristic skeletal changes are present in all patients with SDS and SBDS mutations, but their severity and localization varies with age. No phenotype-genotype correlation was observed.
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PMID:Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS. 1498 68

Shwachman-Diamond syndrome (SDS) is a genetic disorder characterized by pancreatic hypoplasia, recurrent infection, and bone marrow (BM) dysfunction. SDS-patients have an increased frequency of myelodysplasia and leukemic transformation. Unspecific cytogenetic aberrations are a common finding in SDS. However, in a rising number of patients abnormalities of chromosome 7 have been reported, especially an i(7)(q10), which seems to be a non-random chromosome abnormality. Recently, the SDS gene has been mapped at locus 7q11 and subsequently cloned; recurrent mutations have been found. We report a case of SDS with an i(7)(q10) in the BM and two different mutations in the SBDS gene. At the age of 25 years, the patient suffers from mild aplastic anemia but does not show any clinical sign of myelodysplasia or leukemic transformation.
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PMID:SBDS mutations and isochromosome 7q in a patient with Shwachman-Diamond syndrome: no predisposition to malignant transformation? 1547 50

Shwachman-Diamond syndrome (SDS) is an autosomal-recessive disorder characterized by short stature, exocrine pancreatic insufficiency, and hematologic defects. The causative SBDS gene was sequenced in 20 of 23 unrelated patients with clinical SDS. Mutations in the SBDS gene were found in 75%, being identical in 11 patients. Hematologic parameters for all 3 lineages were determined over time such as absolute neutrophil counts (ANCs), granulocyte functions, and erythroid and myeloid colony formation (erythroid burst-forming unit [BFU-E] and granulocyte-monocyte colony-forming unit [CFU-GM]) from hematopoietic progenitor cells, percentage of fetal hemoglobin (HbF), and platelet counts. Persistent neutropenia was present in 43% in the absence of apoptosis and unrelated to chemotaxis defects (in 65%) or infection rate. Irrespective of the ANC in vivo, abnormal CFU-GM was observed in all patients with SDS tested (14 of 14), whereas BFU-E was less often affected (9 of 14). Cytogenetic aberrations occurred in 5 of 19 patients in the absence of myelodysplasia. One child died during allogeneic bone marrow transplantation. In conclusion, neutropenia and defective chemotaxis did not result in severe clinical infection in SDS. CFU-GMs were impaired in all patients tested. From the SBDS sequence data, we conclude that in patients with genetically proven SDS a genotype-phenotype relationship in SDS does not exist in clinical and hematologic terms.
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PMID:Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. 1576 91

Shwachman-Diamond syndrome (SDS) is an inherited marrow failure disorder with varying cytopenia, pancreatic dysfunction, and metaphyseal dysostosis. SDS is also characterized by a risk of myelodysplasia and leukemia in up to one third of the patients. Over the last 5 years, major advances have been made in understanding the bone marrow phenotype. The gene associated with the disease, SBDS, has recently been identified. Herein we provide an update on the clinical features, the hematopoietic defects, and the genetics of the disease as they are currently understood. We also review the diagnostic and therapeutic approaches to the hematological complications in the syndrome.
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PMID:Shwachman-Diamond syndrome. 1604 74

Shwachman-Diamond syndrome (SDS) is an autosomal recessive marrow failure syndrome associated with exocrine pancreatic insufficiency and leukemia predisposition. Bone marrow failure typically manifests with neutropenia, but anemia, thrombocytopenia, or aplastic anemia may also develop. Additional organ systems, such as liver or bone, may also be affected. Clonal cytogenetic abnormalities, particularly those involving chromosome 7 such as monosomy 7 or isochromosome 7, may develop. Mutations in the SBDS gene are found in approximately 90% of patients meeting clinical diagnostic criteria. SBDS is a highly conserved gene of unknown function. Studies of the yeast orthologue YLR022c and structurally related proteins suggest a role in RNA metabolism. In human cells, the SBDS protein localizes to both the cytoplasm and the nucleus, and shuttles in and out of the nucleolus in a cell cycle-dependent manner. A discussion of diagnostic workup, medical management, and treatment is presented.
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PMID:Shwachman-Diamond syndrome. 1682 60

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. SBDS was identified as a causative gene for SDS in 2003, and genetic analyses of SDS have been performed. We performed genetic analysis of 13 Japanese patients with presumed SDS and found that 10 of them had SBDS mutations. Most patients had recurrent mutations (181-184TA-->CT and 258+2T-->C); however, 2 patients had unique mutations (259-1G-->A and 428C-->G). Although genetic analysis is useful for definitive diagnosis and for genetic counseling of SDS patients and families, SDS appears to be a genetically heterogeneous disorder. In addition, presumed SDS patients without SBDS mutations may be included in other disorders.
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PMID:Clinical and genetic analyses of presumed Shwachman-Diamond syndrome in Japan. 1686 4

Mutations in SBDS are responsible for Shwachman-Diamond syndrome (SDS), a disorder with clinical features of exocrine pancreatic insufficiency, bone marrow failure, and skeletal abnormalities. SBDS is a highly conserved protein whose function remains largely unknown. We identified and investigated the expression pattern of the murine ortholog. Variation in levels was observed, but Sbds was found to be expressed in all embryonic stages and most adult tissues. Higher expression levels were associated with rapid proliferation. A targeted disruption of Sbds was generated in order to understand the consequences of its loss in an in vivo model. Consistent with recessive disease inheritance for SDS, Sbds(+/-) mice have normal phenotypes, indistinguishable from those of their wild-type littermates. However, the development of Sbds(-/-) embryos arrests prior to embryonic day 6.5, with muted epiblast formation leading to early lethality. This finding is consistent with the absence of patients who are homozygous for early truncating mutations. Sbds is an essential gene for early mammalian development, with an expression pattern consistent with a critical role in cell proliferation.
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PMID:Loss of the mouse ortholog of the shwachman-diamond syndrome gene (Sbds) results in early embryonic lethality. 1691 46

Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, skeletal abnormalities and hematological dysfunction. The genetic analysis of the SBDS gene and the long-term follow-up of a 37-year-old man with SDS, osteoporosis and type 1 diabetes are reported. Analysis of the SBDS gene revealed a compound heterozygous genotype with 7 mutations. This genotype is the result of the inheritance of abnormal alleles from both healthy parents. We identified putatively non-functional gene conversions from the SBDS pseudogene into the otherwise normal SBDS gene in each of the parentally inherited alleles. The association of SDS and type 1 diabetes mellitus seems to be coincidental and not associated to distinct mutations of the SBDS gene. Osteoporosis in patients with SDS may be the result of a primary defect of the bone metabolism and not of a nutritional problem, although our patient had chronic hypophosphatemia. The long-term follow-up of this patient provides interesting insights into the course of SDS, showing the complexity of genotype-phenotype correlations and the possible influence of other modifying genes and/or environmental factors that might determine the phenotypic presentation of SDS in an individual patient.
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PMID:Compound heterozygous mutations of the SBDS gene in a patient with Shwachman-Diamond syndrome, type 1 diabetes mellitus and osteoporosis. 1710 17


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