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

Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized by a combination of pigmentary and auditory abnormalities. Approximately 20% of WS2 cases are associated with mutations in the gene encoding microphthalmia-associated transcription factor (MITF). MITF plays a critical role in the development of both neural-crest-derived melanocytes and optic cup-derived retinal pigmented epithelium (RPE); the loss of a functional Mitf in mice results in complete absence of all pigment cells, which in turn induces microphthalmia and inner ear deafness. The black-eyed white Mitf mi-bw homozygous mouse normally has a pigmented RPE but lacks melanocytes essential for the pigmentation of the body and hearing. We show here that Mitf mi-bw is caused by an insertion into intron 3 of a 7.2 kb novel L1 element, L1bw, which belongs to an actively retrotransposing TF subfamily. The L1bw insertion reduces the amount of mRNAs for two Mitf isoforms, Mitf-A and Mitf-H, by affecting their overall expression levels and pre-mRNA splicing patterns, while it abolishes mRNA expression of another isoform, Mitf-M, which is specifically expressed in neural-crest-derived melanocytes. The consequence of the L1 insertion in the black-eyed white Mitf mi-bw mouse is that the developmental programme for RPE cells proceeds normally, most likely because of the presence of residual, full-length Mitf-A and Mitf-H proteins, whereas the lack of Mitf-M results in loss of the melanocyte population. The results suggest that melanocyte development depends critically on a single Mitf isoform, Mitf-M, and raise the possibility that specific mutations affecting MITF-M, the human equivalent of Mitf-M, may be responsible for a subset of WS2 conditions.
Hum Mol Genet 1999 Aug
PMID:An L1 element intronic insertion in the black-eyed white (Mitf[mi-bw]) gene: the loss of a single Mitf isoform responsible for the pigmentary defect and inner ear deafness. 1040 Sep 90

Hearing impairment is a common human condition, but we know little about the molecular basis of cochlear function. Shaker-with-syndactylism (sy) is a classic deaf mouse mutant and we show here that a second allele, sy(ns), is associated with abnormal production of endolymph, the fluid bathing sensory hair cells. Using a positional candidate approach, we demonstrate that mutations in the gene encoding the basolateral Na-K-Cl co-transporter Slc12a2 (Nkcc1, mBSC2) cause the deafness observed in sy and sy(ns) mice. This finding provides the molecular basis of another link in the chain of K+recycling in the cochlea, a process essential for normal cochlear function.
Hum Mol Genet 1999 Aug
PMID:Mutation of the Na-K-Cl co-transporter gene Slc12a2 results in deafness in mice. 1040 Oct 8

The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the tRNA(Ser)(UCN) gene is associated with sensorineural deafness, combined in some individuals with a wider syndrome including ataxia and myo-clonus. Previous studies in osteosarcoma cell cybrids revealed only a mild respiratory defect linked to the mutation. We have investigated the biochemical and molecular consequences of the mutation, using a panel of seven osteosarcoma cell cybrids containing 100% mutant mtDNA, plus two cybrids carrying 100% wild-type mtDNA from the same patient. The mutation is associated with a mild growth deficit in selective (galactose) medium that is only significant in combination with a reduced mtDNA copy number, suggesting a mechanism that might modulate clinical phenotype. The mutation results in a 65% drop in the steady-state level of tRNA(Ser)(UCN), but causes at most only a very mild and quantitative abnormality of mitochondrial protein synthesis, associated with modest hypersensitivity to doxycyclin. No evidence for a specific defect in aminoacylation was obtained, and unlike the case with the np 7445 mutation, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparing the np 7472 and np 7445 mutant phenotypes in cultured cells suggests that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA(Ser)(UCN), to which some cells of the auditory system are especially vulnerable.
Hum Mol Genet 1999 Nov
PMID:Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids. 1054 8

Three point mutations of the connexin26 (GJB2) gene associated with hereditary deafness were studied using in vitro expression systems. Mutation M34T results in an amino acid substitution in the first transmembrane domain of the connexin protein, W77R is located in the second transmembrane domain and W44C is in the first extracellular loop. Wild-type and mutated connexin vectors were constructed and transfected into communication-deficient HeLa cells to obtain transient expression of the connexin proteins. Intercellular coupling was subsequently assessed by examining transfer of Lucifer yellow between cells. All three mutations resulted in impaired intercellular coupling. The mechanistic reasons for the functional inadequacies of the mutated proteins were investigated. First, intracellular trafficking and targeting of the expressed connexins were determined by immunohistochemistry. Mutation W77R was inefficiently targeted to the plasma membrane and retained in intracellular stores whereas the other two were targeted to the plasma membrane. Oligomerization assays showed that connexins M34T and W77R failed to assemble efficiently into hexameric gap junction hemichannels, but the W44C mutation did so. A cell-free translation system showed that the mutated proteins were inserted into microsomal membranes but the mutations have different effects on the post-translational properties of the expressed proteins. The results point to the conclusion that mutations in the transmembrane domains of connexin proteins influence gap junction assembly.
Hum Mol Genet 1999 Dec
PMID:Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness. 1055 84

Mutations in the GJB3 gene encoding connexin31 (Cx31) can cause a dominant non-syndromic form of hearing loss (DFNA2). To determine whether mutations at this locus can also cause recessive non-syndromic deafness, we screened 25 Chinese families with recessive deafness and identified in two families affected individuals who were compound heterozygotes for Cx31 mutations. The three affected individuals in the two families were born to non-consanguineous parents and had an early onset bilateral sensorineural hearing loss. In both families, differing SSCP patterns were observed in affected and unaffected individuals. Sequence analysis in both families demonstrated an in-frame 3 bp deletion (423-425delATT) in one allele, which leads to the loss of an isoleucine residue at codon 141, and a 423A-->G transversion in the other allele, which creates an Ile-->Val substitution at codon 141 (I141V). Neither of these two mutations was detected in DNA from 100 unrelated control subjects. The altered isoleucine residue lies within the third conserved alpha-helical transmembrane domain (M3), which is critical for the formation of the wall of the gap junction pore. Both the deletion of the isoleucine residue 141 and its substitution to valine in the two families could alter the structure of M3, and impair the function of the gap junction. The present data demonstrate that, like mutations in connexin26, mutations in Cx31 can lead to both recessive and dominant forms of non-syndromic deafness.
Hum Mol Genet 2000 Jan 01
PMID:Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss. 1058 79

The tub gene is a member of a small, well conserved neuronal gene family of unknown function. Mutations within this gene lead to early-onset blindness and deafness, as well as late-onset obesity and insulin resistance. To test the hypothesis that mutations within other members of this gene family would lead to similar phenotypes as observed in tubby mice, and hence have similar functional properties, we have generated null mutants of the tubby-like protein ( Tulp ) 1 gene by homologous recombination. Similarly to tubby mice, Tulp1 (-/-)mice exhibit an early-onset retinal degeneration with a progressive, rapid loss of photoreceptors, further supporting the notion that previously identified mutations within the human TULP1 gene are indeed causative of retinitis pigmentosa. However, in contrast to tubby mice, Tulp1 (-/-)mice exhibited normal hearing ability and, surprisingly, normal body weight despite the fact that both TUB and TULP1 are expressed in the same neurons within the hypothalamus in areas known to be involved in feeding behavior and energy homeo stasis. However, TUB and TULP1 show a distinctly different staining pattern in the nucleus of these neurons, perhaps explaining the difference in body weight between the Tulp1 (-/-)and tubby mutant mice.
Hum Mol Genet 2000 Jan 22
PMID:Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. 1060 26

Refsum disease is an autosomal recessive neurologic disorder of the lipid metabolism. Major diagnostic clinical findings include retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, increased cerebrospinal fluid protein without pleocytosis, nerve deafness, and cardiac involvement. We have identified a novel protein (PAHX-AP #1) associated with phytanoyl-CoA alpha-hydroxylase (PAHX), a Refsum disease gene product, using the yeast-based two-hybrid assay. The middle portion (amino acids 83-264) of PAHX was used as a bait and a mouse brain cDNA library was searched. The ability of PAHX-AP #1 to interact with PAHX was confirmed using immunoprecipitation and Western blot studies in NIH3T3 cells which stably expressed both PAHX and PAHX-AP #1. Northern and Western blot analyses demonstrated a unique pattern of developmental PAHX-AP #1 expression which was targeted to the adult brain, but ubiquitous expressions of PAHX were observed in all examined tissues. In situ hybridization analyses of the brain showed specific localization of PAHX-AP #1 to the supragranular layer in the cerebral cortex, dentate gyrus, hippocampus, Purkinje cell layer, deep cerebellar nucleus, trigeminal nucleus, abducent nucleus, facial nucleus, cochlear and vestibular nucleus, ganglion cell and nuclear layer of the retina. These data indicate that localization of PAHX-AP #1 in the brain is correlated with central neurologic symptoms of Refsum disease such as retinitis pigmentosa, cerebellar ataxia, nerve deafness and suggest that PAHX-AP #1 may be involved in the development of the central neurologic deficits of Refsum disease.
Brain Res Mol Brain Res 2000 Feb 22
PMID:Identification of a brain specific protein that associates with a refsum disease gene product, phytanoyl-CoA alpha-hydroxylase. 1068 44

There is a dearth of good mouse models for central nervous system (CNS) disorders. However, the development of gene-targeted technology and the recognition of the importance of the mouse as a model organism have led to the development of a range of behavioural tests for mice. Spontaneous mutations in mice have already provided important information about the role of novel gene products in disorders such as epilepsy and deafness. This has provided the impetus to the establishment of large-scale mutagenesis programmes to generate new mutations. Tests of sensory and motor function have previously been most frequently used as these are simple to perform and the phenotypes are relatively obvious. Subtle phenotypes, of relevance to pyschiatric disorders such as anxiety and schizophrenia, can be detected using more complex tests. Screens such as prepulse inhibition and startle have been adapted for mice and these can be run with relatively high throughput using fully automated equipment. Other behaviours such as sleep and circadian rhythms, learning and memory and nociception can also be assessed. New technological advances in non-invasive imaging and neurochemical analyses have meant that these techniques can be readily applied to mouse phenotyping. The use of these screens together with mutagenesis is already beginning to increase the numbers of mouse models of potential relevance to CNS diseases.
Hum Mol Genet 2000 Apr 12
PMID:Towards new models of disease and physiology in the neurosciences: the role of induced and naturally occurring mutations. 1076 12

Normal expression and deafness related changes in expression of NMDAR1 isoforms were examined in the rat superior olivary complex (SOC) using in situ hybridization with S35 labeled oligoprobes. Expression was assessed in three SOC nuclei, the lateral and medial superior olives (LSO, MSO) and the medial nucleus of the trapezoid body (MNTB). Silver grain labeling over principal cells of each region was assessed using METAMORPH image analysis system. Counts were made in ipsi- and contralateral sides after unilateral cochlear ablation and in treated and untreated animals. In the normal SOC, NMDAR1a expression was higher than 1b and 1-2 expression was followed by 1-4 and 1-1, with 1-3 below the level for detection. The levels and ratio were comparable in LSO, MSO and MNTB. Five days after cochlear ablation 1a, 1-1, 1-2 and 1-4 showed significant decreases in the ipsilateral LSO and 1-a and 1-2 showed significant decreases in the contralateral MNTB, with no significant changes in the MSO. At 20 days after deafening, no significant changes were seen for any isoform in any nucleus. The transient deafness-induced decreases in expression of NMDAR1 isoforms correlate with loss of excitation.
Brain Res Mol Brain Res 2000 May 05
PMID:NMDAR1 isoforms in the rat superior olivary complex and changes after unilateral cochlear ablation. 1083 19

Mutations in the CX26 gene (GJB2), encoding the gap-junction protein Connexin-26, have been shown to be the major cause of non-syndromic recessive deafness. Among these mutations, the deletion of a guanine within the stretch of six G between nucleotide positions +30 and +35 of the CX26 cDNA (30delG) accounts for the majority of this kind of deafness. Molecular detection of the 30delG mutation is usually performed by direct sequencing analysis of PCR products or by SSCP. To detect this mutation we developed an easy and reliable method, based on PCR, followed by a non-radioactive sandwich hybridization on microtiter plates. We tested 188 individuals recruited from the genetic counseling service for deaf people at the Pasteur Hospital and at the Armand-Trousseau Children's Hospital, Paris, France between April 1997 and September 1998. Our screening method is simple, uses stable and safe reagents, and employs inexpensive equipment. As such, it is suitable for widespread use in genetic diagnosis.
Mol Cell Probes 2000 Jun
PMID:A simple and reliable method for the detection of the 30delG mutation of the CX26 gene. 1086 Jul 12


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