Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.
Hum Mol Genet 2001 Oct 15
PMID:Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. 1170 37

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

Deletion of thyroid hormone receptor beta (TR beta), a ligand-dependent transcription factor encoded by the Thrb gene, causes deafness and thyroid hyperactivity in Thrb-null (Thrb(tm1/tm1)) mice and in a recessive form of the human syndrome of resistance to thyroid hormone. Here, we have determined that a targeted mutation (Thra(tm2)) in the related Thra gene, encoding thyroid hormone receptor alpha suppresses these phenotypes in mice. Thra encodes a TR alpha 1 receptor which is non-essential for hearing and a TR alpha 2 splice variant of unknown function that neither binds thyroid hormone nor transactivates. The Thra(tm2) mutation deletes TR alpha 2 and concomitantly causes overexpression of TR alpha 1 as a consequence of the exon structure of the gene. Thra(tm2/tm2) mice have normal auditory thresholds indicating that TR alpha 2 is dispensable for hearing, and have only marginally reduced thyroid activity. However, a potent function for the Thra(tm2) allele is revealed upon its introduction into Thrb(tm1/tm1) mice, where it suppresses the auditory and thyroid phenotypes caused by loss of TR beta. These findings reveal a novel modifying function for a Thra allele and suggest that increased expression of TR alpha 1 may substitute for the absence of TR beta. The TR isotypes generated by the distinct Thrb and Thra genes represent a small family of receptors that have diverged to mediate different physiological roles; however, the ability of changes in Thra expression to compensate for loss of Thrb indicates that many functions of these genes remain closely related.
Hum Mol Genet 2001 Nov 01
PMID:Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene. 1172 57

Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness. Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10. The observation that some WS4 patients present with myelination defects of the central and peripheral nervous systems correlates with the recent finding that P(0), a major component of the peripheral myelin, is another transcriptional target of SOX10. These phenotypic features suggest that SOX10 could regulate expression of other genes involved in the myelination process as well. Thus, we tested the ability of SOX10 to regulate expression of MBP, PMP22 and Connexin 32, three major proteins of the peripheral myelin. Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects fail to transactivate the Cx32 promoter. Moreover, we show that a mutation of the Cx32 promoter previously described in a patient with the X-linked form of Charcot-Marie-Tooth (CMTX) disease impairs SOX10 function. In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelin defects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10.
Hum Mol Genet 2001 Nov 15
PMID:Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. 1173 43

A previously unidentified sequence motif has been identified in the products of genes mutated in Miller-Dieker lissencephaly, Treacher Collins, oral-facial-digital type 1 and contiguous syndrome ocular albinism with late onset sensorineural deafness syndromes. An additional homologous motif was detected in a gene product fused to the fibroblast growth factor receptor type 1 in patients with an atypical stem cell myeloproliferative disorder. In total, over 100 eukaryotic intracellular proteins are shown to possess a LIS1 homology (LisH) motif, including several katanin p60 subunits, muskelin, tonneau, LEUNIG, Nopp140, aimless and numerous WD repeat-containing beta-propeller proteins. It is suggested that LisH motifs contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LisH motifs, and their occurrence in homologues of Gbeta beta-propeller subunits, suggests that they are analogues of Ggamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LisH motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. Uncharacterized LisH motif-containing proteins represent candidates for other diseases associated with aberrant microtubule dynamics and defects of cell migration, nucleokinesis or chromosome segregation.
Hum Mol Genet 2001 Nov 15
PMID:A new sequence motif linking lissencephaly, Treacher Collins and oral-facial-digital type 1 syndromes, microtubule dynamics and cell migration. 1173 46

Mutations in four members of the connexin gene family have been shown to underlie distinct genetic forms of deafness, including GJB2 [connexin 26 (Cx26)], GJB3 (Cx31), GJB6 (Cx30) and GJB1 (Cx32). We have found that alterations in a fifth member of this family, GJA1 (Cx43), appear to cause a common form of deafness in African Americans. We identified two different GJA1 mutations in four of 26 African American probands. Three were homozygous for a Leu-->Phe substitution in the absolutely conserved codon 11, whereas the other was homozygous for a Val-->Ala transversion at the highly conserved codon 24. Neither mutation was detected in DNA from 100 control subjects without deafness. Cx43 is expressed in the cochlea, as is demonstrated by PCR amplification from human fetal cochlear cDNA and by RT-PCR of mouse cochlear tissues. Immunohistochemical staining of mouse cochlear preparations showed immunostaining for Cx43 in non-sensory epithelial cells and in fibrocytes of the spiral ligament and the spiral limbus. To our knowledge this is the first alpha connexin gene to be associated with non-syndromic deafness. Cx43 must also play a critical role in the physiology of hearing, presumably by participating in the recycling of potassium to the cochlear endolymph.
Hum Mol Genet 2001 Dec 01
PMID:Mutations in GJA1 (connexin 43) are associated with non-syndromic autosomal recessive deafness. 1174 37

Mohr-Tranebjaerg syndrome (MTS/DFN-1) or deafness/dystonia syndrome results from a mutation in deafness/dystonia protein 1/translocase of mitochondrial inner membrane 8a (DDP1/TIMM8a). DDP1/TIMM8a is similar to a family of yeast proteins in the mitochondrial intermembrane space which mediate the import and insertion of inner membrane proteins. We now show that TIMM8a assembles in a 70 kDa complex in the intermembrane space with TIMM13. DDP1/TIMM8a is not detectable in fibroblasts derived from a patient with a missense mutation in the DDP1/TIMM8a gene; the point mutation results in cysteine-66 being changed to tryptophan-66 in the conserved 'twin CX(3)C' motif. The corresponding mutation in yeast translocase of inner membrane 8p (Tim8p) yields an unstable protein that does not assemble with yeast Tim13p. DDP1/TIMM8a, when expressed with TIMM13 in yeast mitochondria lacking the Tim8p-Tim13p complex, restores Tim23p import, and TIMM8a and TIMM13 can be cross-linked to the hTim23 import intermediate in rat and yeast mitochondria. In a similar manner to Tim8p, TIMM8a seemingly mediates the import of hTim23. Deafness/dystonia syndrome thus may be caused by decreased levels of Tim23 in the mitochondrial inner membrane in affected tissues.
Hum Mol Genet 2002 Mar 01
PMID:Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. 1187 42

Two loci for nonsyndromic recessive deafness located on chromosome 21q22.3 have previously been reported, DFNB8 and DFNB10. Recently a gene which encodes a transmembrane serine protease, TMPRSS3 or ECHOS1, was found to be responsible for both the DFNB8 and DFNB10 phenotypes. To determine the contribution of TMPRSS3 mutations in the general congenital/childhood nonsyndromic deaf population we performed mutation analysis of the TMPRSS3 gene in 448 unrelated deaf patients from Spain, Italy, Greece, and Australia who did not have the common 35delG GJB2 mutation. From the 896 chromosomes studied we identified two novel pathogenic mutations accounting for four mutant alleles and at least 16 nonpathogenic sequence variants. The pathogenic mutations were a 1-bp deletion resulting in a frameshift and an amino acid substitution in the LDLRA domain of TMPRSS3. From this and another study we estimate the frequency of TMPRSS3 mutations in our sample as 0.45%, and approximately 0.38% in the general Caucasian childhood deaf population. However, TMPRSS3 is still an important contributor to genetic deafness in populations with large consanguineous families.
J Mol Med (Berl) 2002 Feb
PMID:Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. 1190 49

The sounds of silence have forever been broken as genetics and genomics approaches in human and model organisms have provided a powerful and rapid entry into gene discovery in the auditory system. An understanding of the complexities and beauty of the biological process of hearing itself is unfolding as genes underlying hereditary hearing impairment are identified. Genes involved in modifying hearing are also being found, and will be critical to a full comprehension of genotype-phenotype relationships. Investigations in the auditory system will provide important insight into how the nervous system decodes molecular information. Deafness represents a common sensory disorder that can interfere dramatically in the acquisition of speech and language in children, and in the quality of life for a growing aged population. As newborn screening for hearing impairment is being implemented in many birth hospitals, the prospects for precise clinical diagnosis, appropriate genetic counseling and proper medical management for auditory disorders has never been at a more exciting crossroad.
Hum Mol Genet 2002 May 15
PMID:Genetics, genomics and gene discovery in the auditory system. 1201 83

Variants in mitochondrial DNA (mtDNA) could be associated with type 2 diabetes because ATP plays a critical role in the production and release of insulin. Diabetes can be precipitated both by mtDNA mutations and by exposure to mitochondrial poisons. The risk of inheriting diabetes from an affected mother is greater than that from an affected father, but this is not explained by maternally inherited diabetes and/or deafness (MIDD) caused by the 3243G : C mtDNA point mutation, which accounts for less than 0.5% of cases of diabetes. A common mtDNA variant (the 16189 variant) is positively correlated with blood fasting insulin, but there are no definitive studies demonstrating that it is associated with diabetes. We demonstrated a significant association between the 16189 variant and type 2 diabetes in a population-based case-control study in Cambridgeshire, UK (n=932, odds ratio=1.61 (1.0-2.7, P=0.048), which was greatly magnified in individuals with a family history of diabetes from the father's side (odds ratio=infinity; P<0.001).
Hum Mol Genet 2002 Jun 15
PMID:Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. 1204 11


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