Amissense mutation in DCDC2 causeshuman recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation

M'hamed Grati, Imen Chakchouk, Qi Ma, Mariem Bensaid, Alexandra Desmidt, Nouha Turki, Denise Yan, Aissette Baanannou, Rahul Mittal, Nabil Driss, Susan Blanton, Amjad Farooq, Zhongmin Lu, Xue Zhong Liu, Saber Masmoudi

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Hearing loss is the most common sensory deficit in humans.We show that a point mutation in DCDC2 (DCDC2a), a member of doublecortin domain-containing protein superfamily, causes non-syndromic recessive deafness DFNB66 in a Tunisian family. Using immunofluorescence on rat inner ear neuroepithelia, DCDC2a was found to localize to the kinocilia of sensory hair cells and the primary cilia of nonsensory supporting cells. DCDC2afluorescence is distributed along the length of the kinocilium with increased density toward the tip. DCDC2a-GFP overexpression in non-polarized COS7 cells induces the formation of long microtubule-based cytosolic cables suggesting a role in microtubule formation and stabilization. Deafness mutant DCDC2a expression in hair cells and supporting cells causes cilium structural defects, such as cilium branching, and up to a 3-fold increase in length ratios. In zebrafish, the ortholog dcdc2b was found to be essential for hair cell development, survival and function. Our results reveal DCDC2a to be a deafness gene and a player in hair cell kinocilia and supporting cell primary cilia length regulation likely via its role in microtubule formation and stabilization.

Original languageEnglish (US)
Pages (from-to)2482-2491
Number of pages10
JournalHuman molecular genetics
Volume24
Issue number9
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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