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A truncated CDC14A retains catalytic structure and phosphatase activity preserving male fertility but causes nonsyndromic deafness

Shabbir, Kanwal LU ; Jackisch, Gina LU ; Belyantseva, Inna A. ; Imran, Muhammad ; Naz, Sadaf ; Sele, Céleste LU ; Murina, Victoriia LU ; Knecht, Wolfgang LU ; Friedman, Thomas B. and Logan, Derek T. LU orcid , et al. (2026) In The Journal of biological chemistry 302(1).
Abstract

Pathogenic variants of human CDC14A (cell division cycle 14A) are associated either with nonsyndromic deafness DFNB32 or HIIMS, hearing impairment infertile male syndrome. The 623-residue CDC14A protein has two globular domains (residues 17-152 and 217-325) and a 278-residue C-terminal intrinsically disordered region (IDR). To date, 16 recessive variants of human CDC14A are associated with hearing loss. Variants affecting the globular N-terminal domains of human CDC14A are associated with HIIMS while mutations in the IDR cause nonsyndromic deafness DFNB32. Here, we tested the hypothesis that human CDC14A c.1033C>T variant, segregating with nonsyndromic deafness in family PKSN10, introduces a premature translation stop codon (p.R345X)... (More)

Pathogenic variants of human CDC14A (cell division cycle 14A) are associated either with nonsyndromic deafness DFNB32 or HIIMS, hearing impairment infertile male syndrome. The 623-residue CDC14A protein has two globular domains (residues 17-152 and 217-325) and a 278-residue C-terminal intrinsically disordered region (IDR). To date, 16 recessive variants of human CDC14A are associated with hearing loss. Variants affecting the globular N-terminal domains of human CDC14A are associated with HIIMS while mutations in the IDR cause nonsyndromic deafness DFNB32. Here, we tested the hypothesis that human CDC14A c.1033C>T variant, segregating with nonsyndromic deafness in family PKSN10, introduces a premature translation stop codon (p.R345X) yet the mRNA escapes nonsense-mediated decay (NMD) and produces sufficient active phosphatase to allow for male fertility. Quantitative analyses of CDC14A mRNA in blood leukocytes from PKSN10 family showed CDC14A transcripts are stable including homozygous (p.R345X) transcripts which evade NMD. To further test this hypothesis, we performed biochemical and structural characterizations of truncated CDC14A (ΔC-CDC14A) protein retaining only residues 1 to 345. Kinetic functional studies and X-ray crystallographic findings of purified ΔC-CDC14A protein indicate that it retains structural integrity and phosphatase activity. Molecular genetic reports of DFNB32 and HIIMS, taken together with structural and functional data in this study, indicate that phosphatase activity of ΔC-CDC14A containing the two globular domains is sufficient for male fertility but insufficient for normal hearing. In addition, we show that the C-terminal IDR of CDC14A is required for normal hearing, likely because it is necessary for normal localization of CDC14A in hair cells.

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type
Contribution to journal
publication status
published
subject
in
The Journal of biological chemistry
volume
302
issue
1
article number
110982
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:41308992
ISSN
1083-351X
DOI
10.1016/j.jbc.2025.110982
language
English
LU publication?
yes
additional info
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
id
5ee39866-09f2-4562-9c48-de9ee535a266
date added to LUP
2025-12-01 09:07:01
date last changed
2026-01-10 02:50:06
@article{5ee39866-09f2-4562-9c48-de9ee535a266,
  abstract     = {{<p>Pathogenic variants of human CDC14A (cell division cycle 14A) are associated either with nonsyndromic deafness DFNB32 or HIIMS, hearing impairment infertile male syndrome. The 623-residue CDC14A protein has two globular domains (residues 17-152 and 217-325) and a 278-residue C-terminal intrinsically disordered region (IDR). To date, 16 recessive variants of human CDC14A are associated with hearing loss. Variants affecting the globular N-terminal domains of human CDC14A are associated with HIIMS while mutations in the IDR cause nonsyndromic deafness DFNB32. Here, we tested the hypothesis that human CDC14A c.1033C&gt;T variant, segregating with nonsyndromic deafness in family PKSN10, introduces a premature translation stop codon (p.R345X) yet the mRNA escapes nonsense-mediated decay (NMD) and produces sufficient active phosphatase to allow for male fertility. Quantitative analyses of CDC14A mRNA in blood leukocytes from PKSN10 family showed CDC14A transcripts are stable including homozygous (p.R345X) transcripts which evade NMD. To further test this hypothesis, we performed biochemical and structural characterizations of truncated CDC14A (ΔC-CDC14A) protein retaining only residues 1 to 345. Kinetic functional studies and X-ray crystallographic findings of purified ΔC-CDC14A protein indicate that it retains structural integrity and phosphatase activity. Molecular genetic reports of DFNB32 and HIIMS, taken together with structural and functional data in this study, indicate that phosphatase activity of ΔC-CDC14A containing the two globular domains is sufficient for male fertility but insufficient for normal hearing. In addition, we show that the C-terminal IDR of CDC14A is required for normal hearing, likely because it is necessary for normal localization of CDC14A in hair cells.</p>}},
  author       = {{Shabbir, Kanwal and Jackisch, Gina and Belyantseva, Inna A. and Imran, Muhammad and Naz, Sadaf and Sele, Céleste and Murina, Victoriia and Knecht, Wolfgang and Friedman, Thomas B. and Logan, Derek T. and Imtiaz, Ayesha}},
  issn         = {{1083-351X}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{The Journal of biological chemistry}},
  title        = {{A truncated CDC14A retains catalytic structure and phosphatase activity preserving male fertility but causes nonsyndromic deafness}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2025.110982}},
  doi          = {{10.1016/j.jbc.2025.110982}},
  volume       = {{302}},
  year         = {{2026}},
}