Molecular Analysis Of Human Hereditary Deafness

National Institute On Deafness And Other Communication Disorders

Investigators

Linked publications, trials & patents

Abstract

(1) We ascertain families with multiple members with nonsyndromic EVA that is not associated with detectable SLC26A4 mutations or Pendred syndrome. Our hypothesis is that these families segregate recessive alleles at one or more other genetic loci that cause nonsyndromic EVA. We are using those families in a combinatorial linkage-based, functional candidate exome sequencing strategy to identify other genetic causes of EVA. We are prioritizing genes for analysis based upon differential expression in the MRCs of the developing endolymphatic sac. (2) We have used CRISPR genome editing to create mouse lines segregating alleles of Slc26a4 with missense mutations identified in human patients. These missense mutations encode Slc26a4 protein (pendrin) with significant residual function. We have successfully generated three different lines and have begun characterizing their phenotypes. The goal of this study is to generate mouse models with hearing loss phenotypes that are less severe than those of the Slc26a4-null line. We also continue to study a dox-inducible Slc26a4-insufficient mouse model of EVA which we have previously reported. We are using these lines to explore the molecular and cellular pathogenesis of hearing loss caused by Slc26a4 mutations. (3) We are searching for proteins that interact with Slc26a4 protein in the endolymphatic sac. We have used the yeast two-hybrid method to screen libraries derived from mouse endolymphatic sac and mouse kidney. We have identified multiple candidates that interact with either the N-terminus or C-terminus of pendrin. We are currently validating these interactions of the most promising and interesting candidates using other methodologies.