Mutations within the COCH gene (encoding the cochlin protein) lead to auditory and vestibular impairment in the DFNA9 disorder. In this study, we describe the genetic mapping of progressive autosomal dominant sensorineural hearing loss first affecting high-frequency auditory thresholds within a human pedigree to the long arm of chromosome 14 in band q12. A maximal pairwise LOD score of 7.08 was obtained with marker D14S1021. We identified a c.1625G > T mutation in exon 12 of COCH that co-segregates with auditory dysfunction in the pedigree. The mutation results in a predicted p.C542F substitution at an evolutionarily conserved cysteine residue in the C-terminus of cochlin. The c.1625G > T transversion in COCH exon 12 represents the first reported mutation outside of the LCCL domain which is encoded by exons 4 and 5. The 542F mutant cochlin is translated and secreted by transfected mammalian cells. Western blot analysis under non-reducing and reducing conditions suggests that the 542F mutation alters intramolecular cochlin disulfide bond formation. In the vestibular system, a progressive horizontal canal hypofunction and a probable saccular otolith challenge were detected in family members with the c.1625G > T COCH alteration. Abnormal central oculomotor test results in family members with the c.1625G > T COCH alteration imply a possible central nervous system change not previously noted in DFNA9 pedigrees harboring mutations within the LCCL domain.

Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6×CBACa) and (MOLF×CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2-129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid-frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid-and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17.

Mutations within MYO7A can lead to recessive and dominant forms of inherited hearing loss. We previously identified a large pedigree (referred to as the HL2 family) with hearing loss that first impacts the low and mid frequencies segregating a dominant MYO7A mutation in exon 17 at DNA residue G2164C. The MYO7A G2164C mutation predicts a nonconservative glycine-toarginine (G722R) amino acid substitution at a highly conserved glycine residue. The degree of low and mid frequency hearing loss varies markedly in the family, suggesting the presence of a genetic modifier that either rescues or exacerbates the primary MYO7A G2164C mutation. Here we describe a single nucleotide polymorphism (SNP) T/C at position ؊4128 in the wild-type MYO7A promoter allele that sorts with the degree of hearing loss severity in the pedigree. Electrophoretic mobility shift assay analysis indicates that the SNP differentially regulates the binding of the YY1 transcription factor with the T ؊4128 allele creat- Large human pedigrees segregating monogenic syndromic and nonsyndromic hearing loss have led to the discovery of Ͼ50 genes harboring mutations underlying the sensory deficient within the pedigree (see the Hereditary Hearing Loss homepage on the Internet). Mutations within myosin VIIA (MYO7A) 2 can lead to both syndromic and nonsyndromic hearing impairment in humans. MYO7A is expressed in the retina, testis, lung, kidney, and inner and outer hair cells of the cochlea (2). In hair cells, MYO7A is found in the actin-rich stereocila bundles, cuticular plate, pericuticular necklace, and cell body (3). MYO7A is also expressed in both type I and type II hair cells of the semicircular canals and utricle (3). Syndromic MYO7A mutations are inherited in a recessive fashion, leading to a diagnosis of Usher type 1B (USH1B), a disease characterized by profound, congenital, sensorineural deafness with progressive retinitis pigmentosa leading to visual loss and vestibular areflexia. Nonsyndromic MYO7A mutations can be inherited in either a recessive (DFNB2, the 2nd autosomal recessive deafness locus identified) or dominant (DFNA11, the 11th autosomal dominant deafness locus identified) manner. Five DFNA11 mutations have been characterized: p.delA886-K887-K888 in a Japanese pedigree (4); p.G772R in an American pedigree (5); N458I in a Dutch pedigree (6); p.R853C in a German pedigree (7); and p.A230V in an Italian pedigree (8).We previously mapped the large hearing-impaired DFNA11 American pedigree (referred to as HL2, for hearing loss family 2) to the long arm of chromosome 11 in band 13.5. A MYO7A mutation in exon 17 at DNA residue G2164C was discovered in the HL2 family. The MYO7A G2164C alteration leads to a predicted nonconservative glycine-to-arginine (G772R) amino acid substitution at a highly conserved glycine residue (5). The MYO7A G2164C mutation is unique as it was the first alteration in MYO7A associated with the uncommon clinical finding of progressive low frequency hearing loss (5). We previously showed that the degree of low and mid frequ...

Background: Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype.

Objectives-To evaluate the auditory, vestibular, and retinal characteristics of a large American DFNA11 pedigree with autosomal dominant progressive sensorineural hearing loss that first impacts the low and mid-frequency auditory range. The pedigree (referred to as the HL2 family) segregates a myosinVIIA (MYO7A) mutation in exon 17 at DNA residue G2164C (MYO7A G2164C ) that appears to be influenced by a genetic modifier that either rescues or exacerbates the MYO7A G2164C alteration. DNA analysis to examine single nucleotide polymorphisms (SNPs) in two candidate modifier genes (ATP2B2 and WFS1) is summarized in this report. Study Design-Family study.Results-The degree of low and mid-frequency hearing loss in HL2 family members segregating the MYO7A G2164C mutation varies from mild to more severe with approximately the same number of HL2 family members falling at each end of the severity spectrum. The extent of hearing loss in HL2 individuals can vary between family generations. Differences in the degree of hearing loss in MYO7A G2164C HL2 family members may be mirrored by vestibular function in at least two of these same individuals. The SNPs examined within ATP2B2 and WFS1 did not segregate with the mild versus more severe auditory phenotype.Conclusions-The severity of the auditory and vestibular phenotypes in MYO7A G2164C HL2 family members may run in parallel suggesting a common modifier gene within the inner ear. The putative MYO7A G2164C genetic modifier is likely to represent a common polymorphism that is not linked tightly to the MYO7A mutation on the MYO7A 2164C allele.

The inner ear contains the developmentally related cochlea and peripheral vestibular labyrinth. Given the similar physiology between these two organs, hearing loss and vestibular dysfunction may be expected to occur simultaneously in individuals segregating mutations in inner ear genes. Twenty-two different genes have been discovered that when mutated lead to non-syndromic autosomal dominant hearing loss. A review of the literature indicates that families segregating mutations in 13 of these 22 genes have undergone formal clinical vestibular testing. Formal assessment revealed vestibular dysfunction in families with mutations in ten of these 13 genes. Remarkably, only families with mutations in the COCH and MYO7A genes self-report considerable vestibular challenges. Families segregating mutations in the other eight genes do not self-report significant balance problems and appear to compensate well in everyday life for vestibular deficits discovered during formal clinical vestibular assessment. An example of a family (referred to as the HL1 family) with progressive hearing loss and clinically-detected vestibular hypofunction that does not report vestibular symptoms is described in this review. Notably, one member of the HL1 family with clinically-detected vestibular hypofunction reached the summit of Mount Kilimanjaro.