Gene/Protein Disease Symptom Drug Enzyme Compound
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We report here, the localization of a new recessive non-syndromal deafness gene (DFNB12) to 10q21-22 by linkage analysis, of a Sunni family. Affected individuals suffer from congenital profound sensorineural hearing loss. A maximum LOD score of 6.40 (theta = 0.00) was obtained with locus D10S535. Analysis of patients carrying recombinations mapped the gene distal to D10S529 and proximal to D10S532, delineating an interval between 11 and 15 cM. Three deaf mouse mutants Jackson circler (jc), Waltzer (v) and Ames waltzer (av) have been localized to the homologous murine region on chromosome 10. Each of these mouse mutants is a candidate mouse model for the DFNB12-associated hearing impairment.
Hum Mol Genet 1996 Jul
PMID:Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22. 881 48

Hereditary hearing impairment affects about 1 in 1000 newborns. In most cases hearing loss is non-syndromic with no other clinical features, while in other families deafness is associated with specific clinical abnormalities. Analysis of large families with non-syndromic and syndromic deafness have been used to identify genes or gene locations that cause hearing impairment. The present report describes a large Norwegian family with autosomal dominant non-syndromic, progressive high tone hearing loss with linkage to 1q21-q23. A maximum LOD score of 7.65 (theta = 0.00) was obtained with the microsatellite marker D1S196. Analysis of recombinant individuals maps the deafness gene (DFNA7) to a 22 cM region between D1S104 and D1S466. The region contains several attractive candidate genes. This report supports the idea of extensive genetic heterogeneity in hereditary hearing impairment and represents the first localization of a deafness gene in a Norwegian family.
Hum Mol Genet 1996 Aug
PMID:Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family. 884 39

Small mutations in the POU domain gene POU3F4 were recently shown to cause X-linked deafness type 3 (DFN3) in nine unrelated males. The POU3F4 gene was found to be located outside four of five deletions associated with DFN3. Two of these deletions were situated more than 400 kb proximal to POU3F4. Employing PCR analysis of sequence tagged sites from this region we initially identified novel deletions in two DFN3 patients. To investigate this chromosomal segment in more detail, we extended a previously established 850 kb cosmid contig in the centromeric direction to a total size of 1500 kb. Cosmids from this contig were hybridized to DNA of 11 unrelated males with DFN3. In two patients, we identified deletions encompassing the POU3F4 gene and variably sized segments of Xq21.1. In six of the nine remaining patients which lacked mutations in the POU3F4 gene, smaller deletions were identified which, with one exception, overlap in a 8 kb segment 900 kb proximal to the POU3F4 gene. In one patient, we identified several small deletions in the vicinity of the 8 kb DNA segment. Together, deletions account for 56% (13/23) of all known DFN3 mutations, most (10/13) of which do not encompass the POU3F4 gene. The combined molecular data suggest that the deletion hot spot region in Xq21.1 contains another DFN3 gene or, alternatively, a sequence element involved in transcriptional regulation of POU3F4.
Hum Mol Genet 1996 Sep
PMID:Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. 887 61

Non-syndromic X-linked deafness is highly heterogeneous. At least five different clinical forms have been described, but only two loci have been mapped. Here we report a Spanish family affected by a previously undescribed X-linked form of hearing impairment. Deafness is non-syndromic, sensorineural, and progressive. In affected males, the auditory impairment is first detected at school age, affecting mainly the high frequencies. Later it evolves to become severe to profound, involving all frequencies for adulthood. Carrier females manifest a moderate hearing impairment in the high frequencies, with the onset delayed to the fourth decade of life. Deafness was assumed to be X-linked dominant, with incomplete penetrance and variable expressivity in carrier females. The family was genotyped for a set of microsatellite markers evenly spaced at intervals of about 10 cM. We found evidence of linkage to markers in the Xp22 region (maximum lod score of 5.30 at theta = 0.000 for DXS8036 and for DXS8022). The position of the novel deafness locus (DFN6) was refined by haplotype analysis. Mapping of the breakpoints in two critical recombinants allowed us to define an interval for DFN6, delimited by DXS7108 on the distal side and by DXS7105 on the proximal side, and spanning a genetic distance of about 15 cM.
Hum Mol Genet 1996 Sep
PMID:A novel locus for non-syndromic sensorineural deafness (DFN6) maps to chromosome Xp22. 887 82

Non-syndromic X-linked deafness is a rare form of genetic deafness accounting for a small proportion of all hereditary hearing loss. It is both clinically and genetically heterogeneous and five loci have been described to date but only two of these have been mapped. DFN2 represents a locus for congenital profound sensorineural hearing loss that has yet to be mapped. We describe a four generation family with this phenotype in which female carriers have a mild/moderate hearing loss affecting the high frequencies. The mutant gene has been mapped to Xq22 using polymorphic microsatellite markers. A maximum two point lod score of 2.91 at theta = 0 was observed with a fully informative dinucleotide repeat at COL4A5, and flanking recombinations were observed at DXS990 and DXS1001.
Hum Mol Genet 1996 Dec
PMID:Mapping of DFN2 to Xq22. 896 63

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.
Hum Mol Genet 1997 Jan
PMID:Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. 900 78

We have studied mitochondrial gene expression and metabolic function in a human lymphoblastoid cell-line homoplasmic for the np 7445, deafness-associated mitochondrial DNA mutation. The mutation maps to the 3' termini of the oppositely oriented genes encoding cytochrome oxidase subunit I (COI) and tRNA-ser(UCN). In comparison with control lymphoblastoid cells, we detected a marked depletion (> 60%) of tRNA-ser(UCN). There was, however, no significant impairment of respiratory function, no alteration to the structure or abundance of COI mRNA or its precursors, and no detectable abnormality of mitochondrial protein synthesis. We also found considerable tissue-variation in the abundance of tRNA-ser(UCN). We propose that the tissue-specific phenotype associated with this mutation results from an inherent deficiency in the processing of the mutant pre-tRNA, that becomes limiting for protein synthesis only in a restricted set of cells of the auditory system in which the tRNA is, for other reasons, already at a critically low level.
Hum Mol Genet 1997 Mar
PMID:Molecular phenotype of a human lymphoblastoid cell-line homoplasmic for the np 7445 deafness-associated mitochondrial mutation. 914 48

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous disease accounting for >2% of the congenitally deaf population. It is characterized by deafness in association with pigmentary anomalies and various defects of neural crest-derived tissues. At least four types are recognized (WS1, WS2, WS3 and WS4) on the basis of clinical and genetic criteria. Two previously described families seemed to delineate a new subtype characterized by WS2 in conjunction with ocular albinism (OA). Since mutations in the MITF gene are responsible for some instances of WS2, we screened for mutations in one of the WS2-OA families and discovered a 1 bp deletion in exon 8 of MITF. OA previously has been associated with compound heterozygosity for a mutant TYR allele and the TYR(R402Q) allele, a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity. In this family, all of the individuals with the OA phenotype are either homozygous or heterozygous for TYR(R402Q), and heterozyous for the 1 bp deletion in MITF This suggests that the WS2-OA phenotype may result from digenic interaction between a gene for a transcription factor (MITF) and a gene that it regulates (TYR).
Hum Mol Genet 1997 May
PMID:Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA). 915 38

An A to G point mutation at nucleotide position 7445 in the mitochondrial DNA genome is associated with maternally-inherited sensorineural deafness in two separate human pedigrees. To determine whether this point mutation [tRNA(SER)UCN)/COI A7445G] led to sensorineural deafness by affecting cellular energy metabolism we investigated the bioenergetic function of mitochondria in lymphoblastoid cultures established from these patients. Even though essentially all of the mitochondrial DNA in these cells contained the mutation at nucleotide position 7445, there was no effect on a number of mitochondrial bioenergetic functions (mitochondrial content, membrane potential in both intact and digitonin-permeabilised cells, cellular ATP/ADP ratios and respiratory enzyme activity) when compared with control cells. The implications of these findings for both the aetiology of the sensorineural deafness associated with the A7445G mtDNA mutation, and the role of bioenergetic defects in mitochondrial DNA diseases in general are discussed.
Biochem Mol Biol Int 1997 Jul
PMID:The effect on mitochondrial function of the tRNA Ser(UCN)/COI A7445G mtDNA point mutation associated with maternally-inherited sensorineural deafness. 924 14

Deafness is the most common form of sensory impairment in humans. Mutations in unconventional myosins have been found to cause deafness in humans and mice. The mouse recessive deafness mutation, Snell's waltzer, contains an intragenic deletion in an unconventional myosin, myosin VI (locus designation, Myo6). The requirement for Myo6 for proper hearing in mice makes this gene an excellent candidate for a human deafness disorder. Here we report the cloning and characterization of the human unconventional myosin VI (locus designation, MYO6) cDNA. The MYO6 gene maps to human chromosome 6q13. The isolation of the human gene makes it now possible to determine if mutations in MYO6 contribute to the pathogenesis of deafness in the human population.
Hum Mol Genet 1997 Aug
PMID:Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice. 925 67


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