Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011053 (deafness)
 10,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report two brothers with a previously undescribed type of mitochondrial encephalomyopathy and associated aminoacidopathy. Both have growth failure, progressive intellectual decline, deafness, neurologic dysfunction, exercise intolerance, lactic acidosis, and abnormal plasma and cerebrospinal fluid amino acid levels (elevated levels of alanine and low levels of threonine, methionine, citrulline, tryptophan, ornithine, arginine, and lysine). A muscle biopsy specimen taken from the younger, more severely affected brother showed abnormal mitochondrial morphology. Activities of the following enzymes in cultured fibroblasts from both boys were normal: pyruvate dehydrogenase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, cytochrome oxidase, reduced nicotinamide-adenine dinucleotide-cytochrome c reductase, and succinate cytochrome c reductase. Fibroblast mitochondria from the younger boy showed undetectable (less than 1% of control values) adenosine triphosphate synthesis with pyruvate and malate, whereas adenosine triphosphate synthesis with succinate was 70% of control values. These data indicate probably deficient activity of complex I of the electron transport chain. The boys' mother has progressive neurosensory hearing loss; their sister is clinically normal. Both mother and sister have many of the biochemical abnormalities found in the boys. It is possible, but not proved, that this disorder is inherited through maternal mitochondria.
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PMID:Mitochondrial encephalomyopathy with associated aminoacidopathy in a male sibship. 273 99

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.
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PMID:Mutations in GJA1 (connexin 43) are associated with non-syndromic autosomal recessive deafness. 1174 37

Otoconia are biominerals within the utricle and saccule of the inner ear that are critical for the perception of gravity and linear acceleration. The classical mouse mutant tilted (tlt) and a new allele, mergulhador (mlh), are recessive mutations that affect balance by impairing otoconial morphogenesis without causing collateral deafness. The mechanisms governing otoconial biosynthesis are not known. Here we show that tlt and mlh are mutant alleles of a novel gene (Otopetrin 1, Otop1), encoding a multi-transmembrane domain protein that is expressed in the macula of the developing otocyst. Both mutants carry single point mutations leading to non-conservative amino acid substitutions that affect two putative transmembrane (TM) domains (tlt, Ala(151)-->Glu in TM3; mlh, Leu(408)-->Gln in TM8). Otop1 and Otop1-like paralogues, Otop2 and Otop3, define a new gene family with homology to the C. elegans and D. melanoganster DUF270 genes.
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PMID:Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1. 1265 73

We report here the biochemical characterization of the deafness-associated mitochondrial tRNA(Ser(UCN)) T7511C mutation, in conjunction with homoplasmic ND1 T3308C and tRNA(Ala) T5655C mutations using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from an African family into human mtDNA-less (rho degrees ) cells. Three cybrids derived from an affected matrilineal relative carrying the homoplasmic T7511C mutation, exhibited approximately 75% decrease in the tRNA(Ser(UCN)) level, compared with three control cybrids. This amount of reduction in the tRNA(Ser(UCN)) level is below a proposed threshold to support a normal rate of mitochondrial protein synthesis in lymphoblastoid cell lines. This defect is likely a primary contributor to approximately 52% reduction in the rate of mitochondrial protein synthesis and marked defects in respiration and growth properties in galactose-containing medium. Interestingly, the T5655C mutation produces approximately 50% reduction in the tRNA(Ala) level in mutant cells. Strikingly, the T3308C mutation causes a significant decrease both in the amount of ND1 mRNA and co-transcribed tRNA(Leu(UUR)) in mutant cells. Thus, mitochondrial dysfunctions caused by the T5655C and T3308C mutations may modulate the phenotypic manifestation of the T7511C mutation. These observations imply that a combination of the T7511C mutation with two mtDNA mutations accounts for the high penetrance of deafness in this family.
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PMID:Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness. 1496 Jul 12

We report the case of a congenitally deaf white male with mild palmoplantar keratoderma, ichthyosiform scaling, follicular hyperkeratosis, and mild keratitis, features consistent with keratitis-ichthyosis-deafness syndrome. His major problem was severe, disfiguring, inflammatory dissecting folliculitis of the scalp, hidradenitis suppurativa, and cystic acne, features comprising the follicular occlusion triad. This unusual phenotype is associated with a novel heterozygous point mutation (C119T) in the gap junction beta2 gene that substitutes a valine for alanine at codon 40 (A40V) in the connexin 26 protein. Through Xenopus oocyte expression studies, this mutant protein was shown to significantly disrupt the function of the specialized gap junctions connecting the cytoplasm of adjacent cells critical for tissue homeostasis. Mutations within the connexin 26 protein are associated with syndromes involving both sensorineural deafness and hyperkeratotic skin disorders. This is the first report of an association between a connexin 26 protein mutation, follicular hyperkeratosis of keratitis-ichthyosis-deafness syndrome, and severe follicular occlusion triad.
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PMID:A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad. 1533 80

Gap-junctional channels are large intercellular aqueous pores formed by head-to-head association of two gap-junctional hemichannels (connexin hexamers), one from each of the adjacent cells. The mechano-transduction of sound waves into electrical impulses occurs in the cochlea, which houses the organ of Corti. Hereditary deafness is frequent and mutations of connexin 26, the predominant connexin of the cochlea, are its most frequent cause. Mutations of R75 cause deafness and disrupt gap-junctional communication. Here, we determined the effects of substitutions of R75 with different residues (alanine, asparagine, aspartic acid, lysine, phenylalanine, tyrosine or tryptophan) on formation of gap-junctional channels and hemichannels. We show that connexin 26 R75 is essential for the formation of gap-junctional channels. Substitution of R75 with aromatic residues yields functional hemichannels that display altered voltage dependence, whereas substitution with other residues yields non-functional hemichannels. The expression of R75 mutants has a dominant negative effect on gap-junctional communication mediated by wild-type connexin 26, independently of the ability of the mutants to form functional gap-junctional hemichannels. Our results show that the arginine located at position 75 of connexin 26 is essential for function, and cannot be replaced by other residues.
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PMID:Mutations of connexin 26 at position 75 and dominant deafness: essential role of arginine for the generation of functional gap-junctional channels. 1694 93

Varitint-waddler (Va and Va(J)) mice are deaf and have vestibular impairment, with inner ear defects that include the degeneration and loss of sensory hair cells. The semidominant Va mutation results in an alanine-to-proline substitution at residue 419 (A419P) of the presumed ion channel TRPML3. Another allele, Va(J), has the A419P mutation in addition to an I362T mutation. We found that hair cells, marginal cells of stria vascularis, and other cells lining the cochlear and vestibular endolymphatic compartments express TRPML3. When heterologously expressed in LLC-PK1-CL4 epithelial cells, a culture model for hair cells, TRPML3 accumulated in lysosomes and in espin-enlarged microvilli that resemble stereocilia. We also demonstrated that wild-type TRPML3 forms channels that are blocked by Gd(3+), have a conductance of 50-70 pS and, like many other TRP channels, open at very positive potentials and thus rectify outwardly. In addition to this outward current, TRPML3(419P) and (I362T+A419P) generated a constitutive inwardly rectifying current that suggests a sensitivity to hyperpolarizing negative potentials and that depolarized the cells. Cells expressing TRPML3(A419P) or (I362T+A419P), but not wild-type TRPML3, died and were extruded from the epithelium in a manner reminiscent of degenerating hair cells in Va mice. The increased open probability of TRPML3(A419P) and (I362T+A419P) at physiological potentials likely underlies hair cell degeneration and deafness in Va and Va(J) mice.
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PMID:The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration. 1816 48

Mutations in mitochondrial DNA (mtDNA) are associated with sensorineural hearing loss. In this study, we traced the origin of the 12S rRNA C1494T mutation through analysis of the clinical, genetic, and molecular characteristics of 13 Han Chinese pedigrees with aminoglycoside-induced and non-syndromic bilateral hearing loss that were selected by C1494T screening in 3133 subjects with non-syndromic hearing impairment from 27 regions of China (13/3133). Clinical evaluation revealed the variable phenotypes of hearing impairment including severity, age-of-onset, and audiometric configuration in these subjects. Through the whole mitochondrial genome DNA sequence analysis, we identified two evolutionarily conservative variants in protein-coding genes: tRNA(Ala) T 5628C and tRNA(Tyr) A5836G mutations. However, the pedigrees with these mutations did not have a higher or lower penetrance of deafness than in other pedigrees. These results suggested that both T 5628C and A5836G mutations might not significantly modify the manifestation of the C1494T mutation. Sequencing analysis of the whole mitochondrial genome of the probands showed that 13 pedigrees from seven different provinces were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms, including haplogroups A, B, D, D4, D4b2, F1, M, M7c, N9a1, and H2b. This result suggested that the C1494T mutation occurred sporadically with multi-origins through the evolution of the mtDNA in China, and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. In addition, the lack of a significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. Therefore, the aminoglycosides is solo well-established factor to contribute to the deafness manifestation of the C1494T mutation, and prevention by avoiding the administration of aminoglycosides in individuals carrying C1494T mutation is the most effective way to protect their vulnerability to deafness.
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PMID:Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation. 1968 3

Mutations in mitochondrial DNA (mtDNA) have been found to be one of the most important causes of sensorineural hearing loss. We report here a clinical, genetic, molecular and biochemical characterization of a Han Chinese pedigree with maternally transmitted nonsyndromic hearing impairment. Seven of nine matrilineal relatives exhibited a variable severity and age-at-onset (8 years old) of hearing loss. Mutational analysis of mtDNA identified the novel homoplasmic tRNA(Ser(UCN)) 7505T>C mutation and other 37 variants belonging to haplogroup F1. The 7505T>C mutation, which is absent in 449 Chinese controls, is located at a highly conserved base-pairing (10A-20U) of tRNA(Ser(UCN)). The abolishment of 10A-20U base-pairing likely alters the tRNA(Ser(UCN)) metabolism. Functional significant of this mutation was supported by approximately 65% reductions in the level of tRNA(Ser(UCN)) observed in the lymphoblastoid cell lines carrying the 7505T>C mutation, compared with the wild-type cell lines. This reduced tRNA level is below the proposed threshold to support a normal respiration in lymphoblastoid cells. Furthermore, the highly conserved tRNA(Ala) 5587T>C and Cytb C93Y variants may have a modifying role of deafness expression associated with the 7505T>C mutation. However, genotyping analysis of nuclear modifier gene TRMU and the prominent deafness-cause gene GJB2 failed to detect any mutations in the member of this family. These data strongly indicate that the novel tRNA(Ser(UCN)) 7505T>C mutation is involved in maternally transmitted hearing loss. However, other genetic, epigenetic or environmental factors may contribute to the phenotypic variability of this family. Our findings will be helpful for counseling families of maternally inherited hearing loss.
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PMID:Maternally inherited hearing loss is associated with the novel mitochondrial tRNA Ser(UCN) 7505T>C mutation in a Han Chinese family. 2015 73

A major challenge in the inner ear research field is to restore hearing loss of both non-genetic and genetic origin. A large effort is being made to protect hair cells from cell death after exposure to noise or drugs that can cause hearing loss. Our research focused on protecting hair cells from cell death occurring in a genetic model for human deafness. POU4F3 is a transcription factor associated with human hearing impairment. Pou4f3 knockout mice (Pou4f3(-/-)) have no cochlear hair cells, resulting in complete deafness. Although the hair cells appear to form properly, they progressively degenerate via apoptosis. In order to rescue the hair cells in the knockout mice, we produced explant cultures from mouse cochleae at an early embryonic stage and treated the cells with z-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a general caspase inhibitor. Hair cell numbers in the knockout mice treated with z-VAD-fmk were significantly higher than in the untreated mice. We found that the time window that z-VAD-fmk has a protective effect is between E14.5 (P=0.001) to E16.5 (P=0.03), but not after E18.5. The source of the surviving hair cells is not due to proliferation, as measured by 5-bromo-2-deoxyuridine (BrdU) labeling, or to supporting cell transdifferentiation to hair cells, since there was no change in supporting cell numbers. Instead, the survival appears to be a direct effect of the anti-apoptotic agent on the dying hair cells with an early developmental window. These results help towards providing a comprehensive understanding of the molecular mechanisms of hair cell death, which might lead to the development of new therapeutic anti-apoptotic agents to alleviate hereditary hearing loss (HL).
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PMID:Anti-apoptotic factor z-Val-Ala-Asp-fluoromethylketone promotes the survival of cochlear hair cells in a mouse model for human deafness. 2039 4


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