Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for Wolfram syndrome (WFS1) has been identified on the short arm of chromosome 4 and subsequently mutations in WFS1 have been described. We have screened 12 patients with Wolfram syndrome from nine Dutch families for mutations in the WFS1-coding region by single-strand conformation polymorphism analysis and direct sequencing. Furthermore, we analyzed the mitochondrial genome for gross abnormalities and the A3243G point mutation in the leucyl-tRNA gene, because Wolfram syndrome shows phenotypic similarities with mitochondrial disease. Seven mutations in WFS1 were identified in six of nine families: two missense mutations, one frameshift mutation, one splice donor site mutation, and three deletions. In addition, a splice variant near the 5'UTR of WFS1 was identified, present in patient as well as control RNA samples in various percentages, alternating the translation initiation consensus sequence. Whether this WFS1 splice variant displays impaired translation efficiency remains to be determined. No MtDNA lesions were identified in any of the Wolfram patients. Our results demonstrate the usefulness of molecular analysis of WFS1 in the refinement of clinical diagnostic criteria for Wolfram syndrome that helps to dissect the clinically overlapping syndromes sharing diabetes mellitus and optic atrophy.
J Mol Diagn 2003 May
PMID:Molecular characterization of WFS1 in patients with Wolfram syndrome. 1270 73

Mutations of the WFS1 gene are responsible for Wolfram syndrome, a rare, recessive disorder characterized by early-onset, non-autoimmune diabetes mellitus, optic atrophy and further neurological and endocrinological abnormalities. The WFS1 gene encodes wolframin, a putative multispanning membrane glycoprotein of the endoplasmic reticulum. The function of wolframin is completely unknown. In order to characterize wolframin, we have generated polyclonal antibodies against both hydrophilic termini of the protein. Wolframin was found to be ubiquitously expressed with highest levels in brain, pancreas, heart and insulinoma beta-cell lines. Analysis of the structural features provides experimental evidence that wolframin contains nine transmembrane segments and is embedded in the membrane in an N(cyt)/C(lum) topology. Wolframin assembles into higher molecular weight complexes of approximately 400 kDa in the membrane. Pulse-chase experiments demonstrate that during maturation wolframin is N-glycosylated but lacks proteolytical processing. Moreover, N-glycosylation appears to be essential for the biogenesis and stability of wolframin. Here we investigate, for the first time, the molecular mechanisms that cause loss-of-function of wolframin in affected individuals. In patients harboring nonsense mutations complete absence of the mutated wolframin is caused by instability and rapid decay of WFS1 nonsense transcripts. In a patient carrying a compound heterozygous missense mutation, R629W, we found markedly reduced steady-state levels of wolframin. Pulse-chase experiments of mutant wolframin expressed in COS-7 cells indicated that the R629W mutation leads to instability and strongly reduced half-life of wolframin. Thus, the Wolfram syndrome in patients investigated here is caused by reduced protein dosage rather than dysfunction of the mutant wolframin.
Hum Mol Genet 2003 Aug 15
PMID:Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. 1291 71

Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. In order to gain insight into the pathophysiology of this disease, we disrupted the wfs1 gene in mice. The mutant mice developed glucose intolerance or overt diabetes due to insufficient insulin secretion in vivo. Islets isolated from mutant mice exhibited a decrease in insulin secretion in response to glucose. The defective insulin secretion was accompanied by reduced cellular calcium responses to the secretagogue. Immunohistochemical analyses with morphometry and measurement of whole-pancreas insulin content demonstrated progressive beta-cell loss in mutant mice, while the alpha-cell, which barely expresses WFS1 protein, was preserved. Furthermore, isolated islets from mutant mice exhibited increased apoptosis, as assessed by DNA fragment formation, at high concentration of glucose or with exposure to endoplasmic reticulum-stress inducers. These results strongly suggest that WFS1 protein plays an important role in both stimulus-secretion coupling for insulin exocytosis and maintenance of beta-cell mass, deterioration of which leads to impaired glucose homeostasis. These WFS1 mutant mice provide a valuable tool for understanding better the pathophysiology of Wolfram syndrome as well as WFS1 function.
Hum Mol Genet 2004 Jun 01
PMID:Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. 1505 6

More than 20 syndromes among the significant and increasing number of degenerative diseases of neuronal tissues are known to be associated with diabetes mellitus, increased insulin resistance and obesity, disturbed insulin sensitivity, and excessive or impaired insulin secretion. This review briefly presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome, Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive megaloblastic anemia syndrome as well as their respective relationship to malignancies, cancer, and aging and the nature of their inheritance (including triplet repeat expansions), genetic loci, and corresponding functional biochemistry. Discussed in further detail are disturbances of glucose metabolism including impaired glucose tolerance and both insulin-dependent and non-insulin-dependent diabetes caused by neurodegeneration in humans and mice, sometimes accompanied by degeneration of pancreatic beta-cells. Concordant mouse models obtained by targeted disruption (knock-out), knock-in, or transgenic overexpression of the respective transgene are also described. Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.
J Mol Med (Berl) 2004 Aug
PMID:Neurodegenerative disorders associated with diabetes mellitus. 1517 61

Diabetic and psychiatric symptoms often appear in patients with Wolfram syndrome, and obligate carriers of WFS1 have increased prevalence of type 2 diabetes and are more likely to require hospitalization for psychiatric illness including bipolar disorder. To identify the polymorphisms in Japanese, we examined a region of approximately 50 kb covering the entire WFS1 gene, and evaluated the patterns of linkage disequilibrium. We found a total of 42 variations including 8 novel coding single nucleotide polymorphisms (A6T, A134A, N159N, T170T, E237K, R383C, V412L, and V503G), 14 novel non-coding polymorphisms, and 2 linkage disequilibrium blocks. We also performed association studies in patients with type 2 diabetes mellitus and patients with bipolar disorder. The haplotype comprising R456 and H611 was most associated with type 2 diabetes (p = 0.013) and the haplotype comprising g. -15503C/T and g. 16226G/A was most associated with bipolar disorder (p = 0.006), but neither reached significant difference after multiple adjustment. These genetic variations and linkage disequilibrium patterns in WFS1 in Japanese should be useful in further investigation of genetic diversities of WFS1 and various related disorders.
Mol Genet Metab 2004 Jul
PMID:Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder. 1523 38

Nonsyndromic hereditary hearing impairment (NSHHI) is a highly heterogeneous disorder with more than 90 loci mapped, of which nearly one-half of the responsible genes are identified. In dominant NSSHI hearing loss is typically biased towards the high frequencies while low-frequency hearing loss is unusual. Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low-frequency loss. We mapped the loci harboring the gene responsible for autosomal dominant low-frequency hearing loss in a multigenerational family. The pedigree of a Swiss family with low-frequency hearing loss was established. Using genomic DNA, DFNA1 and DFNA6/14/38 were excluded by linkage analysis or by direct sequencing of the responsible gene. Genome-wide linkage analysis was performed using commercially available microsatellite markers. Two-point linkage analysis demonstrated linkage to chromosome 5q31, the locus for DFNA15, with a lod score of 6.32 at recombination fraction theta=0 for marker D5S436. Critical recombinations were seen at markers D5S1972 and D5S410. Sequencing of the corresponding gene POU4F3 yielded no pathogenic mutation segregating with the affected members. In addition to Wolfram syndrome gene 1 (DFNA6/14/38) and diaphanous (DFNA1) there is evidence for a third gene involved in low-frequency hearing loss located at DFNA15. Because of the differences in auditory phenotype and the absence of pathogenic mutation in the coding region of POU4F3 it is likely that there is a second gene in 5q31, designated DFNA54, associated with NSHHI.
J Mol Med (Berl) 2004 Nov
PMID:DFNA54, a third locus for low-frequency hearing loss. 1549 91

In this report, we present the haplotype and linkage disequilibrium (LD) pattern in the Collapsin Response Mediator Protein 1 (CRMP1) and Ellis-van Creveld syndrome (EVC) gene region. We genotyped eight different single nucleotide polymorphisms (SNPs) in the CRMP1 and EVC genes in 90 control individuals of diverse ethnicity. The minor allele frequencies ranged from 3.3-49.4%, with most having a frequency >25%. A total of 37 haplotypes were derived from these eight polymorphisms, with only one haplotype having a frequency >10%. Pairwise LD analysis showed a weak but significant LD between markers located about 243 kb apart in this region. The LD was significant between markers spaced about 208 kb apart in EVC, whereas no LD was found between a pair of markers located about 5 kb apart in CRMP1. However, in general, LD correlated with the distance between loci. The CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene, in which mutations also cause low frequency sensorineural hearing loss (LFSNHL). The haplotypes obtained from these polymorphisms will be useful to track the segregation of phenotypes in families with Ellis-van Creveld syndrome, Weyers acrodental dysostosis, LFSNHL and Wolfram syndrome type 1.
Int J Mol Med 2004 Nov
PMID:Haplotype and linkage disequilibrium analysis of the CRMP1 and EVC genes. 1549 64

Genetic predisposition plays an important role in most common psychiatric disorders. The identification of a specific gene associated with a psychiatric illness can lead to improved management of the gene-associated disorder. Mutations in the wolframin gene are associated with mental illness. Many patients with the Wolfram syndrome (WS), who are homozygous or compound heterozygous for wolframin mutations, have severe psychiatric symptoms. In WS families, close blood relatives, who have a high probability of carrying a single wolframin mutation, had a statistically significant excess, over spouse controls, of psychiatric hospitalizations, attempted and completed suicides, and self-reports of mental illness. Since heterozygous carriers of wolframin mutations are relatively frequent in the population according to the general Hardy-Weinberg principle, such mutations might be responsible for the illnesses of many psychiatric patients. The hypothesis that heterozygous carriers of a wolframin mutation are predisposed to psychiatric illness was tested in subjects from 25 WS families. In all, 11 relatives who had psychiatric hospitalizations could be genotyped through mutation analysis. Eight of these carried the wolframin mutation transmitted in their family, significantly (one-sided P=0.0022) more than the 3.0 expected if there were no association between psychiatric hospitalizations and mutations at this locus. All eight mutation-positive subjects had been hospitalized for a major depression. This confirmation of the association is not influenced by confounders, undetected stratification, or genetic heterogeneity. The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 (95% CI 1.9-26.6) for carriers of a single wolframin mutation compared to noncarriers.
Mol Psychiatry 2005 Aug
PMID:Wolframin mutations and hospitalization for psychiatric illness. 1585 62

Recent genetic and genomic studies have greatly advanced our knowledge of the structure and function of genes involved in hearing loss. We are starting to recognize, however, that many of these genes do not appear to follow traditional Mendelian expression patterns and are subject to the effects of allelism and modifier genes. This review presents two genes illustrative of this concept that have varied expression pattern such that they may produce either syndromic or nonsyndromic hearing loss. One of these genes, cadherin 23, produces a spectrum of phenotypic traits, including presbycusis, nonsyndromic prelingual hearing loss (DFNB12), and syndromic hearing loss as part of Usher syndrome (Usher 1D). Missense mutations in CDH23 have been associated with presbycusis and DFNB12, whereas null alleles cause the majority of Usher 1D. Modifier gene products that interact with cadherin 23 also affect the phenotypic spectrum. Similarly, allelsim in the gene encoding wolframin (WFS1) causes either a nonsyndromic dominant low-frequency hearing loss (DFNA6/14/38) or Wolfram syndrome. Missense mutations within a defined region are associated with DFNA6/14/38, while more severe mutations spanning WFS1 are found in Wolfram syndrome patients. The phenotypic spectrum of Wolfram syndrome is also hypothesized to be influenced by modifier genes products. These studies provide increasing evidence for the importance of modifier genes in elucidating the functional pathways of primary hearing loss genes. Characterizing modifier genes may result in better treatment options for patients with hearing loss and define new diagnostic and therapeutic targets.
Anat Rec A Discov Mol Cell Evol Biol 2006 Apr
PMID:Genetics of hearing loss: Allelism and modifier genes produce a phenotypic continuum. 1655 May 84

Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. Herein, we report that pancreatic islets of wfs1-deficient mice exhibit increases in phosphorylation of RNA-dependent protein kinase-like ER kinase, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfs1-deficient MIN6 clonal beta-cells by crossing wfs1-deficient mice with mice expressing simian virus 40 large T antigen in beta-cells. These cells show essentially the same alterations in ER stress responses as wfs1-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of the ER stress response. In contrast, these changes are not observed in heart, skeletal muscle or brown adipose tissues with WFS1-deficiency. The increased ER stress response was accompanied by reduced BrdU incorporation and increased caspase-3 cleavage, indicating impaired cell cycle progression and accelerated apoptotic processes in the mutant islets. These changes are associated with increased expression of the cell cycle regulator p21(CIP1) in wfs1-deficient islets and clonal beta-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21(CIP1). In addition, forced expression of p21(CIP1) resulted in reduced MIN6 beta-cell numbers, suggesting the ER stress-induced increase in p21(CIP1) expression to be involved in beta-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in beta-cells, causing beta-cell loss through impaired cell cycle progression and increased apoptosis.
Hum Mol Genet 2006 May 15
PMID:WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. 1657 99


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