Audiologic Evidence for Further Genetic Heterogeneity at DFNA2

Abstract

A large American family has been mapped to the DFNA2 locus. However, mutation screening of CX31 and KCNQ4, the two genes associated with deafness at this locus, did not identify any mutations. The purpose of this report was to characterize the otologic and audiometric phenotype of this large American family with non-syndromic, autosomal-dominant sensorineural hereditary hearing impairment (HHI). Anamnestic data were obtained, pure-tone audiometry was performed and transient-evoked otoacoustic emissions were recorded. The findings in affected family members were compared to those in unaffected family members and to the respective p50 thresholds of the normal age-matched population. Mutational analysis of the CX26 gene was also performed. The affected members of this family demonstrated progressive symmetric sensorineural hearing impairment. The hearing loss was downward sloping, with mild-to-moderate loss in the low and mid frequencies and severe-to-profound loss in frequencies > 4,000 Hz. The onset of disease was predominantly in the first or early in the second decade. Hearing impairment progressed at approximately 1 dB per year across all frequencies. Transient-evoked otoacoustic emissions revealed a minimal response over all frequencies in affected members but robust responses in all unaffected members. Mutation in the CX26 gene was not present. The affected frequencies observed in this family were similar to those in the original family mapped to DFNA2; however, the age of onset of disease was different and the hearing loss progressed at a slower rate. Therefore, this family provides clinical evidence of genetic heterogeneity at the DFNA2 locus and can serve as a model for age-related hearing loss.

Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia

“…Another possibility is that either other KCNQ family members may provide sufficient biological redundancy to retain normal vestibular function, as inferred from the analysis of genetically altered KCNQ4 mutant mice (Kharkovets, et al, 2000;. Alternatively, similar to other types of progressive high frequency hearing loss (PHFHL), Kcnq4-mediated vestibular impairment in DFNA2 patients might manifest itself as a function of age and/or rate of disease progression (De Leenheer, et al, 2002;Stern and Lalwani, 2002). More sophisticated dynamic tests of eye movement need to be performed on DFNA2 patients to identify any KCNQ4 mutational effect in the canal cristae function.…”

Lack of association between Connexin 31 (GJB3) alterations and sensorineural deafness in Austria

“…Additional DFNA2 linked families investigated were also positive for mutations in KCNQ4 (Van Hauwe et al, 2000;Ensink et al, 2000;Talebizadeh et al, 1999). However, none of the DFNA2 linked families had alterations in the GJB3 gene, which led to the conclusion, that a third gene is involved in hearing impairment in this region (Stern and Lalwani, 2002). These findings would lead to the conclusion that the KCNQ4 gene might be important in some populations.…”

Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss

“…The hearing loss progresses, usually in less than 10 years, to more than 60 dB with middle and low frequencies also involved . By the age of 70, all affected individuals in DFNA2 families have severe to profound hearing loss across all frequencies . There are currently no therapeutic treatments to prevent progressive hearing loss in these patients.…”