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.

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.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cilia / metabolism
  • Cilia / pathology*
  • Female
  • Fluorescent Antibody Technique
  • Hair Cells, Auditory / enzymology
  • Hair Cells, Auditory / pathology*
  • Hearing Loss, Sensorineural / etiology*
  • Hearing Loss, Sensorineural / pathology
  • Humans
  • Larva / genetics
  • Larva / growth & development
  • Male
  • Mice
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Phosphoric Monoester Hydrolases / genetics*
  • Severity of Illness Index*
  • Young Adult
  • Zebrafish / genetics
  • Zebrafish / growth & development

Substances

  • Phosphoric Monoester Hydrolases
  • CDC14A protein, human

Supplementary concepts

  • Deafness, Autosomal Recessive