Great progress has been made in identifying genes responsible for nonsyndromic hearing impairment (NSHI). Routine pure tone audiometry can distinguish conductive from sensorineural hearing loss (SNHL). However, very few studies of NSHI have measured otoacoustic emissions (OAEs) or cochlear micro phonics to assess outer hair cell (OHC) function in individuals with NSHI. Such testing is necessary to differentiate sensory hearing loss (caused by disorders of the cochlear OHC) from neural hearing loss, in which cochlear inner hair cells (IHCs), the auditory nerve, and/or the synapses between IHCs and the auditory nerve are affected. Auditory neuropathy (AN) is a neural type of hearing loss defined by absent or abnormal auditory brainstem responses (ABRs) and preservation of OHC function. 20-30% of patients with AN lose OHC function over time such that the phenotype is no longer distinguishable from SNHL. Little is known about the genetic basis of nonsyndromic AN, although mutations in OTOF (otoferlin) are implicated in recessive AN. We have mapped a novel locus, AUNA1 (auditory neuropathy, nonsyndromic, autosomal dominant, 1) to a 5.47 cM interval on chromosome 13ql4-21 in a large family from the United States. The AUNA1 interval includes a diaphanous gene (DIAPH3) and a protocadherin cluster (PCDH8, PCDH9, PCDH17, and PCDH20). These genes related to known NSHI genes will be our top priority for mutation analysis. We will expand the pedigree and genotype additional markers to narrow the AUNA1 interval. Two homozygous individuals born to affect first cousins will be clinically studied to gain insight into the gene's identity. Positional candidate genes will be screened by DNA sequencing, CSGE analysis, and Northern analysis and real-time PCR to assess for expression differences. Additional candidate genes will be prioritized by inner ear expression seen on micro arrays, which will also allow us to begin to integrate the gene into functional pathways. Additional families linked to AUNA1 locus will be identified by analysis of genome scan data and assessed for AN. Identifying the AUNA1 gene and defining another genetically homogeneous phenotype will be another important step toward developing a clinical algorithm for evaluation of dominant deafness.
| Schoen, Cynthia J; Burmeister, Margit; Lesperance, Marci M (2013) Diaphanous homolog 3 (Diap3) overexpression causes progressive hearing loss and inner hair cell defects in a transgenic mouse model of human deafness. PLoS One 8:e56520 |
| Schoen, Cynthia J; Emery, Sarah B; Thorne, Marc C et al. (2010) Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila. Proc Natl Acad Sci U S A 107:13396-401 |
