Nonsyndromic hearing impairment is associated with a mutation in DFNA5.

Nonsyndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 loci mapped on the human genome, however, only a limited number of genes implicated in hearing loss have been identified. We previously reported linkage to chromosome 7p15 for autosomal dominant hearing impairment segregating in an extended Dutch family (DFNA5). Here, we report a further refinement of the DFNA5 candidate region and the isolation of a gene from this region that is expressed in the cochlea. In intron 7 of this gene, we identified an insertion/deletion mutation that does not affect intron-exon boundaries, but deletes five G-triplets at the 3' end of the intron. The mutation co-segregated with deafness in the family and causes skipping of exon 8, resulting in premature termination of the open reading frame. As no physiological function could be assigned, the gene was designated DFNA5.

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13).

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

Definitive radiotherapy for early glottic carcinoma: prognostic factors and implications for treatment.

PURPOSE: Treatment and disease-related factors were analyzed for their influence on the outcome of patients treated definitively with irradiation (RT) for early glottic carcinoma. METHODS AND MATERIALS: One hundred two patients with stage T1 or T2 glottic carcinomas were treated definitively with RT from December 1983 through September 1993. Median follow-up time was 63 months. Factors analyzed for each patient included age, sex, stage, anterior commissure involvement, surgical alternative, histologic differentiation, field size, total dose, fraction size, and total treatment time. Survival analysis methods were employed to assess the effects of these factors on local control and complication rates. RESULTS: The 5-year local control rates by stage were as follows: T1a, 92%; T1b, 80%; T2a, 94%; and T2b, 23%. By univariate analysis, factors found to have a significant impact on local control were stage, surgical alternative, fraction size, anterior commissure involvement, and overall treatment time. By multivariate analysis, stage, field size, and fraction size were the only significant factors that independently influenced local control. CONCLUSION: The inferior control rate for stage T2b lesions has implications for treatment. Our study supports the conclusion of reports in the literature showing that low fraction size negatively influences outcome in patients with early glottic cancer.

Definitive radiotherapy for early glottic carcinoma: prognostic factors and implications for treatment.

PURPOSE: Treatment and disease-related factors were analyzed for their influence on the outcome of patients treated definitively with irradiation (RT) for early glottic carcinoma. METHODS AND MATERIALS: One hundred two patients with stage T1 or T2 glottic carcinomas were treated definitively with RT from December 1983 through September 1993. Median follow-up time was 63 months. Factors analyzed for each patient included age, sex, stage, anterior commissure involvement, surgical alternative, histologic differentiation, field size, total dose, fraction size, and total treatment time. Survival analysis methods were employed to assess the effects of these factors on local control and complication rates. RESULTS: The 5-year local control rates by stage were as follows: T1a, 92%; T1b, 80%; T2a, 94%; and T2b, 23%. By univariate analysis, factors found to have a significant impact on local control were stage, surgical alternative, fraction size, anterior commissure involvement, and overall treatment time. By multivariate analysis, stage, field size, and fraction size were the only significant factors that independently influenced local control. CONCLUSIONS: The inferior control rate for stage T2b lesions has implications for treatment. Our study supports the conclusions of reports in the literature showing that low fraction size negatively influences outcome in patients with early glottic cancer.

Autosomal dominant nonsyndromic hearing impairment.

Nearly all genes that have been localized for autosomal dominantly inherited hearing impairment are characterized by postlingual hearing loss that is progressive in nature. This auditory phenotype is in contrast to that of genes localized for autosomal recessive hearing impairment, which generally cause nonprogressive severe-to-profound or profound prelingual hearing loss. In most cases, extended pedigrees have been used to localize autosomal dominant deafness genes, To date, 22 autosomal dominant loci have been mapped, and 10 of these genes have been cloned. The functions of these deafness-causing genes are diverse and include transcription factors, extracellular matrix components, ion channels, cytoskeletal components, and unknown functions. Interesting findings include the unexpected expression pattern of some of these genes and the discovery that in some genes, allele variants can cause either isolated hearing loss or syndromic deafness. The greatest challenge for future research will be identifying additional deafness-causing genes and elucidating their function in the inner ear. Am. J. Med. Genet. (Semin. Med. Genet.) 89:167-174, 1999. @ 2000 Wiley-Liss, Inc.

Temporal bone histopathology in connexin 26-related hearing loss.

OBJECTIVE: Mutations in GJB2, a gene that encodes a gap junction protein, Connexin 26 (Cx26), are responsible for approximately one third of sporadic severe-to-profound or profound congenital deafness and half of severe-to-profound or profound autosomal recessive nonsyndromic hearing loss (ARNSHL). Mouse mutants homozygous for knockouts of this gene are nonviable, precluding histopathologic studies of the associated inner ear pathology in this animal model. Therefore, we studied archival temporal bone sections to identify temporal bone donors with Cx26-related deafness. STUDY DESIGN: Temporal bone donors with a history of congenital severe-to-profound or profound deafness were identified in the registry of the Temporal Bone Library at the University of Iowa. Histological findings were interpreted in a blinded fashion. DNA extracted from two celloidin-embedded mid-modiolar sections from each temporal bone was screened for the 35delG Cx26 mutation. The entire coding region of Cx26 was screened for other deafness-causing mutations if the 35delG mutation was detected. RESULTS: Of five temporal bone donors with congenital severe-to-profound deafness, one donor was found to have Cx26-related deafness. This individual was a Cx26 compound heterozygote, carrying the 35delG mutation and a noncomplementary Cx26 missense mutation on the opposing allele. Microscopic evaluation of this temporal bone showed no neural degeneration, a good population of spiral ganglion cells, near-total degeneration of hair cells in the organ of Corti, a detached and rolled-up tectorial membrane, agenesis of the stria vascularis, and a large cyst in the scala media in the region of the stria vascularis. CONCLUSION: This study is the first to report the temporal bone histopathology associated with Cx26-related deafness. Preservation of neurons in the spiral ganglion suggests that long-term successful habilitation with cochlear implants may be possible in persons with severe-to-profound or profound Cx26-related deafness.

Autosomal dominant inherited hearing impairment caused by a missense mutation in COL11A2 (DFNA13).

OBJECTIVE: To analyze the phenotype in a 5-generation DFNA13 family with a missense mutation in the COL11A2 gene that causes autosomal dominant, presumably prelingual, nonsyndromic sensorineural hearing impairment. DESIGN: Family study. SETTING: University hospital department. PATIENTS: Twenty mutation carriers from a large American kindred. METHODS: Cross-sectional analysis using pure-tone threshold measurements at 0.25, 0.5, 1, 2, 4, and 8 kHz. The audiometric configuration was evaluated according to an existing consensus protocol. The significance of features relating to audiometric configuration was tested using 1-way analysis of variance. Progression was evaluated with linear regression analyses of threshold-on-age. RESULTS: Most individuals showed midfrequency (U-shaped) characteristics. The mean threshold in generations IV and V was 44 dB at 1, 2, and 4 kHz (midfrequencies); it was 29 dB at the other frequencies (0.25, 0.5, and 8 kHz). There was no significant progression beyond presbyacusis. CONCLUSION: The trait in this family can be characterized as autosomal dominant, nonprogressive, presumably prelingual, midfrequency sensorineural hearing impairment.

Consumption of a high-galactose diet induces diabetic-like changes in the inner ear.

Diabetes mellitus is a disease that affects multiple organ systems. In our laboratory it has been shown that there is a significant loss of outer hair cells in genetically diabetic rats. Galactosemia can also produce diabetic-like changes. This study was performed to demonstrate whether these changes also occur in the cochlea. Three groups of Sprague-Dawley rats were used and fed either a control diet, a 50% galactose diet, or a 50% galactose diet with the addition of an aldose reductase inhibitor. After 6 months the animals were killed, and the cochleas were removed, fixed, and stained. Diabetes-induced damage was assessed by counting the hair cells and calculating the neuroganglion cell density. The histopathologic changes induced by galactose were manifested as outer hair cell loss and a decrease in neuroganglion cell density. Control animals had the least amount of hair cell loss and the greatest neuroganglion cell density of all three groups. Galactose-only animals demonstrated the most pronounced changes in both hair cell loss and neuroganglion cell degeneration; however, only changes of neuroganglion cell density in the basal turn were significant. The addition of an aldose reductase inhibitor provided inconclusive results in both hair cell determination and neuroganglion cell density; however, generally the inhibitor partially prevented the damage produced by galactose. These results suggest that a high-galactose diet can induce diabetic-like changes in the cochlea.

Connexin 26 as a cause of hereditary hearing loss.

Connexin 26 (Cx26) is an inner ear protein that forms part of the potassium recycling pathway used to maintain the osmotic balance essential for normal auditory function. Mutations in the GJB2 gene, which encodes for the Cx26 protein, recently have been implicated as the cause of up to 50% of hereditary prelingual severe-to-profound nonsyndromic hearing loss. A single mutation that results in the loss of a guanosine nucleotide at position 35, the 35delG mutation, is involved in approximately 97% of cases of Cx26-related deafness. In persons with prelingual severe-to-profound nonsyndromic hearing loss, genetic testing for Cx26-related deafness can establish a diagnosis and obviate the need for a more expensive evaluation. However, if this type of testing is considered, appropriate genetic counseling must be provided and the nuances and limitations of genetic testing must be understood.

A gene for fluctuating, progressive autosomal dominant nonsyndromic hearing loss, DFNA16, maps to chromosome 2q23-24.3.

The sixteenth gene to cause autosomal dominant nonsyndromic hearing loss (ADNSHL), DFNA16, maps to chromosome 2q23-24.3 and is tightly linked to markers in the D2S2380-D2S335 interval. DFNA16 is unique in that it results in the only form of ADNSHL in which the phenotype includes rapidly progressing and fluctuating hearing loss that appears to respond to steroid therapy. This observation suggests that it may be possible to stabilize hearing through medical intervention, once the biophysiology of deafness due to DFNA16 is clarified. Especially intriguing is the localization of several voltage-gated sodium-channel genes to the DFNA16 interval. These cationic channels are excellent positional and functional DFNA16 candidate genes.

Localization of a gene for otosclerosis to chromosome 15q25-q26.

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi-generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease-causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.

High prevalence of symptoms of Menière's disease in three families with a mutation in the COCH gene.

We report the genetic analysis of one large Belgian and two small Dutch families with autosomal dominant non-syndromic progressive sensorineural hearing loss associated with vestibular dysfunction. Linkage studies in the Belgian family mapped the disease to the DFNA9 locus on chromosome 14. Mutation analysis of the COCH gene, which is responsible for DFNA9, revealed a missense mutation changing a highly conserved residue. One of the patients, who had an earlier age of onset in comparison with most of the affected family members, was shown to be homozygous for the mutation. After the mutation was found in the Belgian family, we discovered that the same missense mutation was also present in two Dutch families with similar cochleo-vestibular symptoms. In all three families with hearing loss and imbalance problems, >25% of the patients showed additional symptoms, including episodes of vertigo, tinnitus, aural fullness and hearing loss. Clinically, these symptoms are consistent with the criteria for Menière's disease. The importance of genetic factors in Menière's disease has been suggested on many occasions, but this study is the first report of a mutation in a gene leading to the symptoms of Menière's disease in a significant portion of the carriers. The COCH gene may be one of the genetic factors contributing to Menière's disease and the possibility of a COCH mutation should be considered in patients with Menière's disease symptoms.

Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.

We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.