title: A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation.
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. DCDC2a fluorescence 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.
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: M'hamed
authors.initials: M
authors.lastname: Grati
authors.affiliation: Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie.
authors.forename: Imen
authors.initials: I
authors.lastname: Chakchouk
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie.
authors.forename: Mariem
authors.initials: M
authors.lastname: Bensaid
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Desmidt
authors.affiliation: Service Otorhinolaryngologie, Hôpital Universitaire Mahdia, Mahdia, Tunisie.
authors.forename: Nouha
authors.initials: N
authors.lastname: Turki
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Yan
authors.affiliation: Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie.
authors.forename: Aissette
authors.initials: A
authors.lastname: Baanannou
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Mittal
authors.affiliation: Service Otorhinolaryngologie, Hôpital Universitaire Mahdia, Mahdia, Tunisie.
authors.forename: Nabil
authors.initials: N
authors.lastname: Driss
authors.affiliation: Dr John T. Macdonald Foundation Department of Human Genetics, and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33146, USA and.
authors.forename: Susan
authors.initials: S
authors.lastname: Blanton
authors.affiliation: Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.affiliation: Department of Biology, University of Miami, Miami, FL 33146, USA.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA, xliu@med.miami.edu saber.masmoudi@cbs.rnrt.tn.
authors.forename: Xue Zhong
authors.initials: XZ
authors.lastname: Liu
authors.affiliation: Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax, Tunisie, xliu@med.miami.edu saber.masmoudi@cbs.rnrt.tn.
authors.forename: Saber
authors.initials: S
authors.lastname: Masmoudi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002874:Chromosome Mapping; D002923:Cilia / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D017930:Genes, Reporter; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment; D015027:Zebrafish
chemical_list: C510451:DCDC2 protein, human; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins