A frameshift mutation of Grhl2 alters susceptiblity to noise induced hearing loss: A mouse model for DFNA28 deafness

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	NIDCD	GEN/GENOM-17

Authors

• R.J. Morell
• S. Naz
• J.E. Bird
• S. Shah
• T. Conrad
• T.B. Friedman

Abstract

A frameshift mutation of GRHL2 (c.1609_1610insC) was proposed as the cause of autosomal dominant progressive hearing loss (DFNA28) in a single North American family (Peters, 2002). No other mutations in GRHL2 causing hearing loss have been reported, although association of an intronic polymorphism with age-related hearing loss has been posited (Van Laer, 2008). In mouse, we engineered a mutation equivalent to the DFNA28 allele (Grhl2TminsC). We hypothesized that a Grhl2 mutation might cause increased susceptibility to either age-related hearing loss (AHL) or noise-induced hearing loss (NIHL). We established back-crossed Grhl2TminsC lines on C57Bl6 (susceptible to both NIHL and AHL), 129SvEv (resistant to NIHL, susceptible to AHL) and CBA/CaJ (resistant to AHL). We found that Grhl2TminsC heterozygote mice differ in their susceptibility to NIHL when compared to wild-type littermates. Also, scratch assays performed on primary cell cultures established from mutant mice show delayed wound closure compared to wild-type. Given the role of Grainyhead transcription factors in epithelial development and wound healing we hypothesize that the DFNA28 mutation affects an epithelial maintenance or wound repair mechanism in the cochlea. We are using ChIP-Seq and RNA-Seq to identify the genes regulated by Grhl2 that might mediate wound repair in the cochlea.

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