Journal article
CDC14A phosphatase is essential for hearing and male fertility in mouse and human
Human molecular genetics, Vol.27(5), pp.780-798
03/01/2018
DOI: 10.1093/hmg/ddx440
PMCID: PMC6059191
PMID: 29293958
Abstract
The Cell Division-Cycle-14 gene encodes a dual-specificity phosphatase necessary in yeast for exit from mitosis. Numerous disparate roles of vertebrate Cell Division-Cycle-14 (CDC14A) have been proposed largely based on studies of cultured cancer cells in vitro. The in vivo functions of vertebrate CDC14A are largely unknown. We generated and analyzed mutations of zebrafish and mouse CDC14A, developed a computational structural model of human CDC14A protein and report four novel truncating and three missense alleles of CDC14A in human families segregating progressive, moderate-to-profound deafness. In five of these families segregating pathogenic variants of CDC14A, deaf males are infertile, while deaf females are fertile. Several recessive mutations of mouse Cdc14a, including a CRISPR/Cas9-edited phosphatase-dead p.C278S substitution, result in substantial perinatal lethality, but survivors recapitulate the human phenotype of deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies and sound-transducing stereocilia. Auditory hair cells of postnatal Cdc14a mutants develop normally, but subsequently degenerate causing deafness. Kinocilia of germ-line mutants of mouse and zebrafish have normal lengths, which does not recapitulate the published cdc14aa knockdown morphant phenotype of short kinocilia. In mutant male mice, degeneration of seminiferous tubules and spermiation defects result in low sperm count, and abnormal sperm motility and morphology. These findings for the first time define a new monogenic syndrome of deafness and male infertility revealing an absolute requirement in vivo of vertebrate CDC14A phosphatase activity for hearing and male fertility.
Details
- Title: Subtitle
- CDC14A phosphatase is essential for hearing and male fertility in mouse and human
- Creators
- Hela Azaiez - Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, 52242, IA, USAAyesha Imtiaz - School of Biological Sciences, University of the Punjab, Lahore 54590, PakistanInna A Belyantseva - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USAKevin T Booth - The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, 52242, IA, USAAlisha J Beirl - Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USAElizabeth A Wilson - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USARichard J H Smith - The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, 52242, IA, USACristina Fenollar-Ferrer - Laboratory of Molecular and Cellular Neurobiology, Section on Molecular and Cellular Signaling, National Institute of Mental Health, NIH, Bethesda, MD 20892, USARasheeda Bashir - School of Biological Sciences, University of the Punjab, Lahore 54590, PakistanIhtisham Bukhari - School of Biological Sciences, University of the Punjab, Lahore 54590, PakistanAmal Bouzid - Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax 3451, TunisiaUzma Shaukat - Center of Excellence in Molecular Biology, University of the Punjab, Lahore 54590, PakistanKimia Kahrizi - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 1987513834, IranHossein Najmabadi - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 1987513834, IranAzra Maqsood - School of Biological Sciences, University of the Punjab, Lahore 54590, PakistanTracy S Fitzgerald - Mouse Auditory Testing Core Facility, NIH, Bethesda, MD 20892, USAAbdelaziz Tlili - Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax 3451, TunisiaRafal Olszewski - Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USAMerete Lund - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USATaimur Chaudhry - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USAAtteeq U Rehman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USAMatthew F Starost - Division of Veterinary Resources, National Institutes of Health, Bethesda, MD 20892, USAAli M Waryah - Center of Excellence in Molecular Biology, University of the Punjab, Lahore 54590, PakistanMichael Hoa - Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USALijin Dong - Genetic Engineering Core, National Eye Institute, NIH, Bethesda, MD 20892, USARobert J Morell - Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USASheikh Riazuddin - Laboratory for Research in Genetic Diseases, Burn Centre, Allama Iqbal Medical College, University of Health Sciences, Lahore 54590, PakistanSaber Masmoudi - Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax 3451, TunisiaKatie S Kindt - Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USASadaf Naz - School of Biological Sciences, University of the Punjab, Lahore 54590, PakistanThomas B Friedman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.27(5), pp.780-798
- DOI
- 10.1093/hmg/ddx440
- PMID
- 29293958
- PMCID
- PMC6059191
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 1460-2083
- eISSN
- 1460-2083
- Publisher
- England
- Grant note
- R01 DC003544 / NIDCD NIH HHS Z01 DC000039 / Intramural NIH HHS R01 DC012049 / NIDCD NIH HHS R01 DC000086 / NIDCD NIH HHS T32 DC000039 / NIDCD NIH HHS ZIC EY000458 / Intramural NIH HHS R01 DC002842 / NIDCD NIH HHS R01 TW007608 / FIC NIH HHS
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007157402771
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