Alternative titles; symbols
HGNC Approved Gene Symbol: CDC14A
Cytogenetic location: 1p21.2 Genomic coordinates (GRCh38) : 1:100,345,001-100,520,277 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p21.2 | Deafness, autosomal recessive 32, with or without immotile sperm | 608653 | Autosomal recessive | 3 |
In S. cerevisiae, the cdc14 gene is essential for cell cycle progression. Analysis of the cdc14 point of action suggests that the protein acts in late nuclear division, and may play a role in preparation for DNA replication during the subsequent cell cycle. By searching an EST database for cdc14 homologs, Li et al. (1997) identified partial CDC14A and PTEN (601728) cDNAs. They used the CDC14A cDNA to screen heart and fetal libraries and recovered additional CDC14A cDNAs and a CDC14B (603505) cDNA. Like the yeast cdc14 protein, CDC14A, CDC14B, and PTEN contain a putative protein-tyrosine phosphatase (PTPase) domain. The predicted 580-amino acid CDC14A protein shares 64% identity with yeast cdc14, while PTEN is more closely related to a different yeast gene. Using a chimeric GFP-CDC14A protein, Li et al. (1997) localized CDC14A specifically to the nucleus of mammalian cells. Northern blot analysis revealed that the CDC14A gene is expressed as 1.8- and 4.4-kb mRNAs in all tissues, with the strongest expression in kidney, heart, and skeletal muscle. The authors observed additional transcripts in some tissues, which they considered to be either alternatively spliced CDC14A mRNAs or transcripts from related genes.
Delmaghani et al. (2016) stated that 6 different CDC14A transcripts resulting from alternative splicing had been reported. The largest deduced protein contains 623 amino acids.
By immunofluorescence experiments on mouse inner ear between embryonic day 18.5 and postnatal day 21, Delmaghani et al. (2016) demonstrated the presence of Cdc14a from early stages of hair-bundle differentiation onward, along both the transient kinocilia of developing cochlear hair cells and the persistent kinocilia of vestibular hair cells.
Imtiaz et al. (2018) analyzed expression and localization of Cdc14a in the mouse inner ear and observed association with the upper one-third of stereocilia as well as tubulin-rich structures in hair cells, including kinocilia, basal bodies, and the pericuticular ring. In zebrafish neuromast cells, endogenous cdc14a was also present in kinocilia of hair cells. In transfected COS-7 cells and supporting cells of the organ of Corti, CDC14A was associated with filamentous tubulin in the cytoplasm. Using a LacZ reporter as a proxy for cell type-specific expression of Cdc14a in mice, the authors observed prominent activity in the organ of Corti and vestibular sensory epithelia, consistent with endogenous Cdc14a localization that persisted at least until postnatal day 60. Signal was also detected in cells of the lamina spiralis ossea and in spiral ganglions.
By genomic sequence analysis, Wong et al. (1999) determined that the CDC14A gene contains 16 exons.
Delmaghani et al. (2016) stated that the CDC14A gene contains 18 exons.
By radiation hybrid analysis, Wong et al. (1999) mapped the CDC14A gene to chromosome 1p21.
Li et al. (1997) found that recombinant CDC14A exhibited the kinetic properties of dual-specific phosphatases (see 602038) in vitro. Plasmids expressing CDC14A specifically rescued the cell cycle-arrest phenotype of a cdc14 mutant yeast strain. Li et al. (1997) stated that the structural and functional equivalence of the yeast and human CDC14 PTPases suggests that the human protein may play an essential role in controlling mammalian cell cycle events.
Using derivatives of an osteosarcoma cell line conditionally expressing CDC14A, Mailand et al. (2002) determined that both overexpression and downregulation of CDC14A caused aberrant chromosome partitioning into daughter cells. CDC14A interacted with interphase centrosomes, and this interaction was independent of microtubules and CDC14A phosphatase activity. The interaction required nuclear export, however, and disruption of the nuclear export signal (NES) led to CDC14A accumulation in nucleoli. Conditional overexpression of CDC14A resulted in premature centrosome splitting and formation of supernumerary mitotic spindles, and these effects were independent of CDC14A phosphatase activity. Downregulation of endogenous CDC14A by short inhibitory RNA duplexes induced mitotic defects, including impaired centrosome separation and failure to undergo cytokinesis.
The inner centromere-like protein (INCENP; 604411) forms a complex with the evolutionarily conserved family of Aurora B kinases (see 604970). The INCENP-Aurora complex helps coordinate chromosome segregation, spindle behavior, and cytokinesis during mitosis. INCENP-Aurora associates with kinetochores in metaphase and with spindle microtubules in anaphase. Pereira and Schiebel (2003) demonstrated that the conserved phosphatase CDC14 regulates the yeast INCENP-Aurora complex, Sli15-lpl1. CDC14 dephosphorylated Sli15 and thereby directed the complex to spindles. Activation of CDC14 by separase (604143) was sufficient for Sli15 dephosphorylation and relocalization. CDC14 not only regulates mitotic exit but also modulates spindle midzone assembly through Sli15-lpl1.
Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC; see 608473), triggers the destruction of securin (604147), thereby allowing separase, a protease, to disrupt sister chromatid cohesion. Holt et al. (2008) demonstrated that the cyclin-dependent kinase-1 (CDK1; 116940)-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14, Holt et al. (2008) concluded that their results supported the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, they showed that mutations that disrupt securin phosphoregulation decreased the synchrony of chromosome segregation. Holt et al. (2008) also concluded that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister chromatid separation with changes in spindle dynamics.
Clemente-Blanco et al. (2009) demonstrated that Cdc14, a protein phosphatase required for nucleolar segregation and mitotic exit, inhibits transcription of yeast ribosomal genes (rDNA) during anaphase. The phosphatase activity of Cdc14 is required for RNA polymerase I (Pol I) inhibition in vitro and in vivo. Moreover, Cdc14-dependent inhibition involves nucleolar exclusion of Pol I subunits. The authors demonstrated that transcription inhibition is necessary for complete chromosome disjunction, because ribosomal RNA transcripts block condensin binding to rDNA, and show that bypassing the role of Cdc14 in nucleolar segregation requires in vivo degradation of nascent transcripts. Clemente-Blanco et al. (2009) concluded that transcription interferes with chromosome condensation, not the reverse, and that budding yeast, like most eukaryotes, inhibit Pol I transcription before segregation as a prerequisite for chromosome condensation and faithful genome separation.
In affected individuals from a consanguineous Iranian family with autosomal recessive deafness mapping to chromosome 1p21 (DFNB32; 608653), Delmaghani et al. (2016) identified homozygosity for a nonsense mutation in the CDC14A gene (R376X; 603504.0001) that segregated fully with disease in the family and was not found in controls or in public databases. (The form of deafness mapped by Delmaghani et al. (2016) was previously designated DFNB105.) Whole-exome sequencing of 115 unrelated individuals from Maghreb with severe or profound congenital deafness identified a Mauritanian patient with profound deafness who was homozygous for another nonsense mutation in CDC14A (R339X; 603504.0002).
In affected individuals from 8 consanguineous families segregating autosomal recessive deafness, Imtiaz et al. (2018) identified homozygosity for mutations in the CDC14A gene (see, e.g., 603504.0001 and 603504.0003-603504.0007). Deaf men from 5 of the families reported infertility, and semen analyses showed high percentages of immotile sperm with abnormal morphology; deaf women exhibited normal fertility.
Delmaghani et al. (2016) performed knockdown of cdc14a in zebrafish and found no gross morphologic defects of the inner ear at 3 days postfertilization; however, they observed significant shortening of hair cell kinocilia.
Imtiaz et al. (2018) generated 3 different mutant alleles of mouse Cdc14a and observed high rates of perinatal lethality for homozygotes and compound heterozygotes. The rare survivors showed only residual hearing at low frequencies on postnatal day (P) 16, and hearing loss progressed to profound deafness at all frequencies by P90. Distortion-product otoacoustic emissions were absent at all ages tested, indicating a loss of outer hair cell (OHC) function in the mutant mice as early as P16; however, endocochlear potentials were normal, consistent with intact stria vascularis function. Deaf male mice were infertile, whereas homozygous mutant deaf females had many litters of healthy pups. Histologic examination of mutant testis showed subcapsular degeneration of the seminiferous tubules, with loss of spermatogenic cells, vacuolization of sustentacular cells, and partial collapse of the lumina. There were retained spermatid heads at the basement membrane and/or aggregates of spermatids around residual bodies, and a significant decrease in epididymal sperm count with an increased number of abnormal sperm and excessive fragmentation, in mutant males compared to control littermates. Staining to visualize the inner-ear cytoskeleton of homozygous and compound heterozygous mutants showed degeneration of inner and OHCs of the apical turn starting at P17, with fusion of some stereocilia together. By P90, 50% of mutant inner and OHCs were missing, compared to 0.5% for wildtype littermates; however, the mutant mice were profoundly deaf at P90, suggesting that an additional malfunction in the auditory system might contribute to the hearing loss. Scanning electron microscopy of inner ears of mice homozygous for a CRISPR/Cas9-generated C278S mutation in Cdc14a that ablates phosphatase catalytic activity showed changes similar to those due to other mutant alleles of Cdc14a, with fusion of stereocilia and degeneration of hair cells by P60. The homozygous mice were profoundly deaf, and male mice were infertile with degeneration of seminiferous tubules and low sperm counts. The authors noted that reduced numbers of homozygous C278S survivors suggested that phosphatase catalytic activity also promotes perinatal viability.
In affected members of a consanguineous Iranian family with severe prelingual deafness (DFNB32; 608653), Delmaghani et al. (2016) identified homozygosity for a c.1126C-T transition (c.1126C-T, NM_033312.2) in exon 11 of the CDC14A gene, resulting in an arg376-to-ter (R376X) substitution. The mutation segregated fully with disease in the family and was not found in 150 Iranian controls or in the 1000 Genomes Project or Exome Variant Server databases. The reported pedigree included a deaf man with an obligate carrier daughter, who entered into a consanguineous marriage and had 2 deaf children.
Imtiaz et al. (2018) reported a consanguineous Iranian family (MORL2) in which 2 sisters and a brother had autosomal recessive prelingual sensorineural moderate to profound hearing loss due to homozygosity for the R376X mutation. The deaf brother had a biologic son.
In a male patient from Mauritia with profound deafness (DFNB32; 608653), Delmaghani et al. (2016) identified homozygosity for a c.1015C-T transition (c.1015C-T, NM_033312.2) in exon 11 of the CDC14A gene, resulting in an arg339-to-ter (R339X) substitution. The mutation was not found in 105 controls, including 50 Mauritanian individuals. The fertility of the proband was not reported.
In a large consanguineous Tunisian pedigree (FT1) segregating autosomal recessive prelingual sensorineural moderate to profound hearing loss (DFNB32; 608653), originally studied by Masmoudi et al. (2003), Imtiaz et al. (2018) identified homozygosity for a c.935G-A transition (c.935G-A, NM_033312.2) in exon 10 of the CDC14A gene, resulting in an arg312-to-gln (R312Q) substitution at a highly conserved residue within the core dual-specificity phosphatase domain. The mutation segregated fully with disease in the pedigree. The fertility status of the 3 affected men in the family was reported as unknown.
In 2 sisters and a brother from an Iranian family (MORL1) with prelingual sensorineural moderate to profound hearing loss (DFNB32; 608653), Imtiaz et al. (2018) identified homozygosity for a c.934C-G transversion (c.934C-G, NM_033312.2) in exon 10 of the CDC14A gene, resulting in an arg312-to-gly (R312G) substitution at a highly conserved residue within the core dual-specificity phosphatase domain. The mutation segregated fully with disease in the family. Semen analysis in the 29-year-old deaf brother showed 68 million sperm/mL, of which 67% were immotile and 20% exhibited abnormal morphology.
In 5 affected members of a large consanguineous Pakistani family (HLRB11) with prelingual sensorineural moderate to profound progressive hearing loss (DFNB32; 608653), Imtiaz et al. (2018) identified homozygosity for a 1-bp deletion (c.376delT, NM_033312.2) in exon 5 of the CDC14A gene, causing a frameshift predicted to result in a premature termination codon (Tyr126Ilefs64Ter). The fertility status of 1 of the 2 deaf men in the family was reported as unknown. The other, a 25-year-old man, had been married 3 years but had no offspring; semen analysis yielded no sperm, but white and red blood cells were observed in the sample at levels indicative of infection.
In 2 affected men from a consanguineous Pakistani family (HPK1) with prelingual sensorineural moderate hearing loss (DFNB32; 608653), who used hearing aids in oral conversation, Imtiaz et al. (2018) identified homozygosity for a splice site mutation (c.839-3C-G, NM_033312.2) in intron 9 of the CDC14A gene. Analysis of leukocyte mRNA from affected and unaffected family members revealed 2 aberrant mRNA transcripts, one that skips exon 10 and another that uses a cryptic exon 10 acceptor splice site, both causing frameshifts predicted to result in premature termination codons (Lys279fs16Ter and Lys279fs10Ter, respectively). The fertility status of 1 of the deaf men was reported as unknown; the second deaf man had been married 11 years with no offspring, and semen analysis showed 16 to 50 million sperm/mL, of which 65 to 75% were immotile and 60% exhibited abnormal morphology.
In 2 affected brothers and a sister from a consanguineous Pakistani family (PKSN10) with prelingual sensorineural moderate hearing loss (DFNB32; 608653), who used hearing aids in oral conversation, Imtiaz et al. (2018) identified homozygosity for a c.1033C-T transition (c.1033C-T, NM_033312.2) in exon 11 of the CDC14A gene, resulting in an arg345-to-ter (R345X) substitution. Both brothers had biologic offspring.
Clemente-Blanco, A., Mayan-Santos, M., Schneider, D. A., Machin, F., Jarmuz, A., Tschochner, H., Aragon, L. Cdc14 inhibits transcription by RNA polymerase I during anaphase. Nature 458: 219-222, 2009. [PubMed: 19158678] [Full Text: https://doi.org/10.1038/nature07652]
Delmaghani, S., Aghaie, A., Bouyacoub, Y., El Hachmi, H., Bonnet, C., Riahi, Z., Chardenoux, S., Perfettini, I., Hardelin, J.-P., Houmeida, A., Herbomel, P., Petit, C. Mutations in CDC14A, encoding a protein phosphatase involved in hair cell ciliogenesis, cause autosomal-recessive severe to profound deafness. Am. J. Hum. Genet. 98: 1266-1270, 2016. [PubMed: 27259055] [Full Text: https://doi.org/10.1016/j.ajhg.2016.04.015]
Holt, L. J., Krutchinsky, A. N., Morgan, D. O. Positive feedback sharpens the anaphase switch. Nature 454: 353-357, 2008. [PubMed: 18552837] [Full Text: https://doi.org/10.1038/nature07050]
Imtiaz, A., Belyantseva, I. A., Beirl, A. J., Fenollar-Ferrer, C., Bashir, R., Bukhari, I., Bouzid, A., Shaukat, U., Azaiez, H., Booth, K. T., Kahrizi, K., Najmabadi, H., and 19 others. CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum. Molec. Genet. 27: 780-798, 2018. [PubMed: 29293958] [Full Text: https://doi.org/10.1093/hmg/ddx440]
Li, L., Ernsting, B. R., Wishart, M. J., Lohse, D. L., Dixon, J. E. A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast. J. Biol. Chem. 272: 29403-29406, 1997. [PubMed: 9367992] [Full Text: https://doi.org/10.1074/jbc.272.47.29403]
Mailand, N., Lukas, C., Kaiser, B. K., Jackson, P. K., Bartek, J., Lukas, J. Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation. Nature Cell Biol. 4: 317-322, 2002. Note: Erratum: Nature Cell Biol. 8: 897 only, 2006. [PubMed: 11901424] [Full Text: https://doi.org/10.1038/ncb777]
Masmoudi, S., Tlili, A., Majava, M., Ghorbel, A. M., Chardenoux, S., Lemainque, A., Zina, Z. B., Moala, J., Mannikko, M., Weil, D., Lathrop, M., Ala-Kokko, L., Drira, M., Petit, C., Ayadi, H. Mapping of a new autosomal recessive nonsyndromic hearing loss locus (DFNB32) to chromosome 1p13.3-22.1. Europ. J. Hum. Genet. 11: 185-188, 2003. [PubMed: 12634867] [Full Text: https://doi.org/10.1038/sj.ejhg.5200934]
Pereira, G., Schiebel, E. Separase regulates INCENP-Aurora B anaphase spindle function through Cdc14. Science 302: 2120-2124, 2003. [PubMed: 14605209] [Full Text: https://doi.org/10.1126/science.1091936]
Wong, A. K. C., Chen, Y., Lian, L., Ha, P. C., Peterson, K., Laity, K., Carillo, A., Emerson, M., Heichman, K., Gupte, J., Tavtigian, S. V., Teng, D. H.-F. Genomic structure, chromosomal location, and mutation analysis of the human CDC14A gene. Genomics 59: 248-251, 1999. [PubMed: 10409437] [Full Text: https://doi.org/10.1006/geno.1999.5863]