Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wolfram syndrome (WS), a rare autosomal recessive neurodegenerative disorder, results in most cases from mutations in the WFS1 gene. In this study, a total of 19 patients with Wolfram syndrome and 36 relatives from 17 families were screened for mutations in the WFS1 gene. WFS1 mutations were identified on both alleles in 16 of 19 patients and on 1 allele of 3 patients, showing that WFS1 is the major gene involved in WS in the french population. We identified 25 different mutations, twelve of which were novel. We found 6 frameshift mutations, 6 nonsense mutations, 6 missense mutations, 6 in-frame deletions, and one new homozygous mutation in the splice donor site of exon 7 (c.861+1G>A) resulting in a frameshift. Most patients were compound heterozygotes. No common founder mutation or mutational hot spot were found in the WFS1 gene. Although most mutations occurred in exon 8, in some cases molecular screening requires analysis of all exons, including the non-coding exon 1. We also identified 3 new polymorphisms. Furthermore, genotype-phenotype correlation suggests that the presence of inactivating mutations on both alleles may be associated with an early onset of diabetes mellitus.
 ...
PMID:Wolfram syndrome in French population: characterization of novel mutations and polymorphisms in the WFS1 gene. 1560 10

Wolfram syndrome is a rare diffuse neurodegenerative disorder also known as DIDMOAD due to its characteristics of diabetes insipidus, diabetes mellitus, optic nerve atrophy and deafness. It is also associated with a wide variety of abnormalities of the central nervous system, urinary tract and endocrine glands. It may be familial or sporadic. Imaging findings include absence of the short T1 nature of the pituitary posterior lobe, atrophy of the optic nerve, chiasma, and tracts. Atrophy of the brain stem and cerebellum has also been reported. We describe a 15-year-old boy and an 11-year-old girl with Wolfram syndrome who were siblings from a diabetes mellitus family. They received regular insulin control at our hospital and had symptoms of frequent urinary tract infection and diabetes insipidus. Magnetic resonance imaging revealed marked pons and cerebellar atrophy. Optic nerve and chiasma atrophy was also noted.
 ...
PMID:Imaging characteristics of familial Wolfram syndrome. 1576 70

Wolfram syndrome is a rare neurodegenerative disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD). A wide spectrum of abnormalities of the central nervous system, urinary tract and endocrine glands is also observed. We report cranial MRI findings in a 32-year-old female patient with Wolfram syndrome. In addition to the classical features, including absence of the normal high signal of the neurohypophysis, atrophy of visual pathways, the brainstem, cerebellum and cerebral cortex, we observed bilateral hyperintensity on proton density- and T2- weighted images related to the optic radiations in the periventricular white matter of the temporal and parieto-occipital lobes, which may reflect gliosis pathologically.
 ...
PMID:Cranial magnetic resonance imaging of Wolfram (DIDMOAD) syndrome. 1584 65

Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.
Diabetes Res Clin Pract 2005 Aug
PMID:Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome. 1600 63

Wolfram Syndrome is an autosomal recessive degenerative disorder of the neuroendocrine system. Diabetes mellitus is its lead symptom. Patients show mutations in the wolframin (WFS1) gene coding for a hydrophobic transmembrane protein of 890 amino acids. This protein was preliminarily localised in the endoplasmatic reticulum (ER) in cells of mice and rats. Mice lacking the WFS1 gene display degeneration of pancreatic beta-cells following induction of ER stress. We here used antibodies against substructures of the wolframin protein in order to analyse its expression and localisation. Expression was detected in both pancreatic beta-cells and the limbic system of mice. Using the rat insulinoma cell line RIN 5AH and fractionated mouse brain tissue, we confirmed wolframin localisation to the endoplasmic reticulum. Expression profiling on patient's primary fibroblasts revealed down-regulation of the diabetes associated plasma membrane glycoprotein (PC-1) gene, and up-regulation of fibulin-3, a gene connected to senescence. However, cell proliferation was indistinguishable from non-mutated cells. In contrast to data obtained on murine pancreatic islets, we found no increased apoptosis following induction of ER stress but rather by staurosporine treatment in the absence of WFS1 function. This indicates a new role of WFS1 deficiency in programmed cell death.
 ...
PMID:Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells. 1608 5

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.
 ...
PMID:Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. 1615 13

In Wolfram syndrome, a rare form of juvenile diabetes, pancreatic beta-cell death is not accompanied by an autoimmune response. Although it has been reported that mutations in the WFS1 gene are responsible for the development of this syndrome, the precise molecular mechanisms underlying beta-cell death caused by the WFS1 mutations remain unknown. Here we report that WFS1 is a novel component of the unfolded protein response and has an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells. WFS1 encodes a transmembrane glyco-protein in the ER. WFS1 mRNA and protein are induced by ER stress. The expression of WFS1 is regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response. WFS1 is normally up-regulated during insulin secretion, whereas inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction. These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1.
 ...
PMID:WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. 1619 29

Wolfram syndrome is a rare, autosomal recessive disorder characterized by early-onset diabetes mellitus, optic atrophy and neurological and endocrinological abnormalities. A 47-year-old Japanese man with frequent severe hypoglycemic episodes was diagnosed as Wolfram syndrome based on clinical features and laboratory data. He had positive glutamic acid decarboxylase (GAD) and insulinoma-associated antigen-2 (IA-2) antibodies, both uncommon in this syndrome. Genetic analysis revealed that WFS1 gene of the patient has a homozygous 5 base pairs (AAGGC) insertion at position 1279 in exon 8, causing a frameshift at codon 371 leading to premature termination at codon 443.
Diabetes Res Clin Pract 2006 Aug
PMID:A novel mutation of WFS1 gene in a Japanese man of Wolfram syndrome with positive diabetes-related antibodies. 1644 62

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.
 ...
PMID:WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. 1657 99

Wolfram syndrome (WS, OMIM 22233), is a rare, autosomal recessive, and neurodegenerative disease. The syndrome is also known as DIDMOAD, the acronym for diabetes insipidus diabetes mellitus, optic atrophy and deafness, which summarizes the main clinical features, among many others, in WS patients. The gene associated with the syndrome, called WFS1, is located in the 4p16.1 region. The WFS1 gene encodes for a transmembrane protein located in the endoplasmic reticulum. Although the function of the WFS1 protein remains unknown, it is thought to be related with intracellular calcium homeostasis. The pattern of presentation of WS suggested the existence of mitochondrial impairment. Mitochondrial DNA rearrangements were detected in some patients, thus confirming that hypothesis. Recently, a particular WS phenotype has been described linked with the long arm of chromosome 4. This work aims to summarize the current knowledge about this disease that causes a heterogeneous phenotype and has a complex molecular aetiology.
 ...
PMID:Wolfram/DIDMOAD syndrome, a heterogenic and molecularly complex neurodegenerative disease. 1663 90


<< Previous 1 2 3 4 5 6 7 8 9 10