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

作者：Delmaghani Sedigheh; Aghaie Asadollah; Bouyacoub Yosra; El Hachmi Hala; Bonnet Crystel; Riahi Zied; Chardenoux Sebastien; Perfettini Isabelle; Hardelin Jean Pierre; Houmeida Ahmed; Herbomel Philippe; Petit Christine^*

来源：American Journal of Human Genetics, 2016, 98(6): 1266-1270.

DOI：10.1016/j.ajhg.2016.04.015

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.

• 出版日期2016-6-2