Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Dominantly inherited progressive hearing loss DFNA38 is caused by heterozygosity for a novel mutation in WFS1, the gene for recessively inherited Wolfram syndrome. Wolfram syndrome is defined by juvenile diabetes mellitus and optic atrophy and may include progressive hearing loss and other neurological symptoms. Heterozygotes for other Wolfram syndrome mutations generally have normal hearing. Dominant deafness defined by DFNA38 is more severe than deafness of Wolfram syndrome patients and lacks any syndromic features. In a six-generation kindred from Newfoundland, Canada, WFS1 Ala716Thr (2146 G-->A) was shared by all deaf members of the family and was specific to deaf individuals. The causal relationship between this missense mutation and deafness was supported by two observations based on haplotype and mutation analysis of the kindred. First, a relative homozygous for the mutation was diagnosed at age 3 years with insulin-dependent diabetes mellitus, the central feature of Wolfram syndrome. Second, two relatives with normal hearing had an identical haplotype to that defining DFNA38, with the exception of the base pair at position 2146. Other rare variants of WFS1 co-inherited with deafness in the family could be excluded as disease-causing mutations on the basis of this hearing-associated haplotype. The possibility that 'mild' mutations in WFS1 might be a cause of non-syndromic deafness in the general population should be explored.
Hum Mol Genet 2001 Oct 15
PMID:Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. 1170 38

Dominant optic atrophy (DOA) is the most common form of inherited optic neuropathy. Although heterogeneous, a major locus has been mapped to chromosome 3q28 and the responsible gene, OPA1, was recently identified. OPA1 is a mitochondrial dynamin-related GTPase implicated in the formation and maintenance of the mitochondrial network. To date, 62 mutations have been identified in a total of 201 DOA patients. Most of them (90%) are distributed from exons 8 to 28 with a majority in the GTPase domain (54%). None were found in the alternatively spliced exons 4, 4b, and 5b. Half of them are truncative mutations (50%) with a frequent recurrent allele, c.2708delTTAG. Most missense mutations (81%) cluster within the putative GTPase domain. Various pathogenic mechanisms may play a role in OPA1 DOA. Truncative mutations in the N-terminal region and perhaps missense mutations in the GTPase domain lead to a loss of function of the encoded protein and haplotype insufficiency. However, there is a cluster of truncation mutations in the in C-terminus, a putative dimerization domain, that could act through a dominant negative effect. The findings that OPA1-type DOA, as Leber optic neuropathy, is caused by the impairment of a mitochondrial protein address the question of the vulnerability of the retinal ganglion cell in response to mitochondrial defects.
Mol Genet Metab 2002 Feb
PMID:OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. 1185 28

Type III 3-methylglutaconic aciduria (MGA) (MIM 258501) consists of early bilateral optic atrophy, later development of spasticity, extrapyramidal dysfunction and occasionally cognitive deficits, and urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. The presence of the disorder in an Iraqi-Jewish genetic isolate led to mapping of the OPA3 gene to chromosome 19q13.2-q13.3, followed by isolation of the gene itself. OPA3 consists of two exons and codes for a peptide of 179 amino acids. Iraqi-Jewish patients with type III MGA are homozygous for a splice site founder mutation in OPA3 (IVS1-1G>C) which abolishes mRNA expression in fibroblasts. Here we report a novel mutation in OPA3 (320-337del) in a Kurdish-Turkish patient with optic atrophy and 3-methylglutaconic and 3-methylglutaric aciduria, previously carrying the diagnosis of type IV MGA. We conclude that type III MGA occurs in patients of non-Iraqi-Jewish ancestry, and should be considered in patients with type IV MGA that have optic atrophy and ataxia.
Mol Genet Metab 2002 Jul
PMID:3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. 1212 33

The structure of mitochondria is highly dynamic and depends on the balance of fusion and fission processes. Deletion of the mitochondrial dynamin-like protein Mgm1 in yeast leads to extensive fragmentation of mitochondria and loss of mitochondrial DNA. Mgm1 and its human ortholog OPA1, associated with optic atrophy type I in humans, were proposed to be involved in fission or fusion of mitochondria or, alternatively, in remodeling of the mitochondrial inner membrane and cristae formation (Wong, E. D., Wagner, J. A., Gorsich, S. W., McCaffery, J. M., Shaw, J. M., and Nunnari, J. (2000) J. Cell Biol. 151, 341-352; Wong, E. D., Wagner, J. A., Scott, S. V., Okreglak, V., Holewinske, T. J., Cassidy-Stone, A., and Nunnari, J. (2003) J. Cell Biol. 160, 303-311; Sesaki, H., Southard, S. M., Yaffe, M. P., and Jensen, R. E. (2003) Mol. Biol. Cell, in press). Mgm1 and its orthologs exist in two forms of different lengths. To obtain new insights into their biogenesis and function, we have characterized these isoforms. The large isoform (l-Mgm1) contains an N-terminal putative transmembrane segment that is absent in the short isoform (s-Mgm1). The large isoform is an integral inner membrane protein facing the intermembrane space. Furthermore, the conversion of l-Mgm1 into s-Mgm1 was found to be dependent on Pcp1 (Mdm37/YGR101w) a recently identified component essential for wild type mitochondrial morphology. Pcp1 is a homolog of Rhomboid, a serine protease known to be involved in intercellular signaling in Drosophila melanogaster, suggesting a function of Pcp1 in the proteolytic maturation process of Mgm1. Expression of s-Mgm1 can partially complement the Deltapcp1 phenotype. Expression of both isoforms but not of either isoform alone was able to partially complement the Deltamgm1 phenotype. Therefore, processing of l-Mgm1 by Pcp1 and the presence of both isoforms of Mgm1 appear crucial for wild type mitochondrial morphology and maintenance of mitochondrial DNA.
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PMID:Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. 1270 84

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

Optic nerve involvement in metabolic disorders often results from apoptosis of cells that form or support the optic nerve, the retinal ganglion cell (RGC) axons, the myelin-forming oligodendrocytes, or the supporting vascular system. Given their high energy demands and the long course of their axons, RGCs are particularly sensitive to intracellular metabolic defects. Defects in energy metabolism, formation of reactive oxygen species, and storage of metabolites can all cause apoptosis of RGCs, decreased myelin formation of oligodendrocytes and increased pressure on the optic nerve. Clinically, the loss of RGC axons manifests as pale optic nerves. In general, the ophthalmologist can identify the underlying cause of an optic atrophy by careful examination, neuro-imaging, and family history. In some cases, however, the diagnosis proves elusive. In these instances, and especially when optic atrophy is accompanied by other systemic involvement, a metabolic disorder should be considered. Here, we review the underlying mechanisms of optic atrophy and its significance in metabolic disorders. Early identification of optic atrophy aids the diagnosis and subsequent management of the underlying condition, including anticipation of symptoms, genetic counseling, and possible therapeutic interventions. For many metabolic disorders, molecular testing is available.
Mol Genet Metab
PMID:Optic atrophies in metabolic disorders. 1619 17

Mitochondria provide a myriad of services to the cell, including energy production, calcium buffering and regulation of apoptosis. How these diverse functions are coordinated among the hundreds of mitochondria in a given cell is largely unknown, but is probably dependent on the dynamic nature of mitochondria. In this review, we explore the latest developments in mitochondrial dynamics in mammals. These studies indicate that mitofusins and OPA1 are essential for mitochondrial fusion, whereas Fis1 and Drp1 are essential for mitochondrial fission. The overall morphology of the mitochondrial population depends on the relative activities of these two sets of proteins. In addition to the regulation of mitochondrial shape, these molecules also play important roles in cell and tissue physiology. Perturbation of mitochondrial fusion results in defects in mitochondrial membrane potential and respiration, poor cell growth and increased susceptibility to cell death. These cellular observations may explain why mitochondrial fusion is essential for embryonic development. Two inherited neuropathies, Charcot-Marie-Tooth type 2A and autosomal dominant optic atrophy, are caused by mutations in mitofusin 2 and OPA1, suggesting that proper regulation of mitochondrial dynamics is particularly vital to neurons. Mitochondrial fission accompanies several types of apoptotic cell death and appears important for progression of the apoptotic pathway. These studies provide insight into how mitochondria communicate with one another to coordinate mitochondrial function and morphology.
Hum Mol Genet 2005 Oct 15
PMID:Emerging functions of mammalian mitochondrial fusion and fission. 1624 27

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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