2. Academic Validation
  3. Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness

Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness

  • Am J Hum Genet. 2016 Jun 2;98(6):1266-1270. doi: 10.1016/j.ajhg.2016.04.015.
Sedigheh Delmaghani 1,  Asadollah Aghaie 2,  Yosra Bouyacoub 3,  Hala El Hachmi 4,  Crystel Bonnet 2,  Zied Riahi 2,  Sebastien Chardenoux 1,  Isabelle Perfettini 1,  Jean-Pierre Hardelin 1,  Ahmed Houmeida 4,  Philippe Herbomel 5,  Christine Petit 6
Affiliations

Affiliations

  • 1 Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 75015 Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, Complexité du Vivant, 75005 Paris, France.
  • 2 UMRS 1120, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, Complexité du Vivant, 75005 Paris, France; Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, 75012 Paris, France.
  • 3 Institut Pasteur de Tunis, LR11IPT05, Biomedical Genomics and Oncogenetics Laboratory, Tunis 1002, Tunisia; Université de Monastir, Institut Supérieur de Biotechnologie, BP 56 Monastir 5000, Tunisia.
  • 4 Laboratoire de Biochimie et Biologie Moléculaire, Faculté des Sciences et Techniques, Nouakchott 5026, Mauritania.
  • 5 Sorbonne Universités, Université Pierre et Marie Curie, Complexité du Vivant, 75005 Paris, France; Unité des Macrophages et Développement de l'Immunité, Institut Pasteur, 75015 Paris, France; UMR 3738, Centre National de la Recherche Scientifique, 75015 Paris, France.
  • 6 Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 75015 Paris, France; UMRS 1120, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, Complexité du Vivant, 75005 Paris, France; Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, 75012 Paris, France; Collège de France, 75005 Paris, France. Electronic address: [email protected].
PMID: 27259055 DOI: 10.1016/j.ajhg.2016.04.015
Abstract

By genetic linkage analysis in a large consanguineous Iranian family with eleven individuals affected by severe to profound congenital deafness, we were able to define a 2.8 Mb critical interval (at chromosome 1p21.2-1p21.1) for an autosomal-recessive nonsyndromic deafness locus (DFNB). Whole-exome sequencing allowed us to identify a CDC14A biallelic nonsense mutation, c.1126C>T (p.Arg376(∗)), which was present in the eight clinically affected individuals still alive. Subsequent screening of 115 unrelated individuals affected by severe or profound congenital deafness of unknown genetic cause led us to identify another CDC14A biallelic nonsense mutation, c.1015C>T (p.Arg339(∗)), in an individual originating from Mauritania. CDC14A encodes a protein tyrosine Phosphatase. Immunofluorescence analysis of the protein distribution in the mouse inner ear showed a strong labeling of the hair cells' kinocilia. By using a morpholino strategy to knockdown cdc14a in zebrafish larvae, we found that the length of the kinocilia was reduced in inner-ear hair cells. Therefore, deafness caused by loss-of-function mutations in CDC14A probably arises from a morphogenetic defect of the auditory sensory cells' hair bundles, whose differentiation critically depends on the proper growth of their kinocilium.

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