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

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.

Integrin α8 and Pcdh15 act as a complex to regulate cilia biogenesis in sensory cells

“…Recently, it has been shown that mutations in two kinociliary proteins, Cdc14a and Dcdc2, are associated with human recessive deafness (Delmaghani et al, 2016;Grati et al, 2015). Zebrafish morphants (MOs) for dcdc2 and cdc14a showed kinocilium abnormalities with the concomitant defects in hair cell morphology and function, reinforcing the notion of a direct involvement of primary cilia in hair cell function (Delmaghani et al, 2016;Grati et al, 2015).…”

“…In vertebrates, primary cilia are implicated in several developmental pathways and act as signaling centers mediating intercellular communications (Ezratty et al, 2011;Breunig et al, 2008;Delling et al, 2016). Dysfunction of cilia, due to mutations in ciliary proteins or proteins involved in vesicular transport, is associated with a broad spectrum of human disorders that affect sensory neuron physiology (hearing/balance, olfaction and vision), as well as organ development and function (Delmaghani et al, 2016;Grati et al, 2015;Jagger et al, 2011;Rachel et al, 2012).…”

“…Although the kinocilium is important for the establishment of hair bundle polarity (Jones and Chen, 2008), it may also play additional roles as a modulator of mechanotransduction activity in immature hair cells as well as a linkage coupling the hair cell bundle to components of the extracellular matrix (ECM) (Roberts et al, 1988;Kindt et al, 2012). Recently, it has been shown that mutations in two kinociliary proteins, Cdc14a and Dcdc2, are associated with human recessive deafness (Delmaghani et al, 2016;Grati et al, 2015). Zebrafish morphants (MOs) for dcdc2 and cdc14a showed kinocilium abnormalities with the concomitant defects in hair cell morphology and function, reinforcing the notion of a direct involvement of primary cilia in hair cell function (Delmaghani et al, 2016;Grati et al, 2015).…”

Protein localization screening in vivo reveals novel regulators of multiciliated cell development and function

“…Human CERKL mutations are associated with retinitis pigmentosa, a known ciliopathy (Tuson et al, 2004), but the mechanism of CERKL action is poorly defined; we founbd that Cerkl localized to axonemes, suggesting a novel avenue of inquiry. Likewise, Rfx transcription factors are linked to hearing loss (Elkon et al, 2015), and we identified three proteins with cilia and/or basal body localization that are encoded by genes that are known to be involved in human deafness (Elmod3, Lrtomta, Cdc14a) (Ahmed et al, 2008;Delmaghani et al, 2016;Jaworek et al, 2013).…”

Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients

“…Approximately 120 genes responsible for non-syndromic HL have been identified so far [1,2]. Since 2016, the gene CDC14A (OMIM: *603504, ENSG00000079335) has been associated with autosomal recessive non-syndromic deafness-32 (DFNB32, OMIM: #608653) [3]. Two years later, it was recognized as causing hearing impairment and infertile male syndrome (HIIMS) [4].…”