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Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans

Azoospermia is a significant cause of male infertility, with non-obstructive azoospermia (NOA) being the most severe type of spermatogenic failure. NOA is mostly caused by congenital factors, but our understanding of its genetic causes is very limited. Here, we identified a frameshift variant (c.201...

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Autores principales: Liu, Junyan, Rahim, Fazal, Zhou, Jianteng, Fan, Suixing, Jiang, Hanwei, Yu, Changping, Chen, Jing, Xu, Jianze, Yang, Gang, Shah, Wasim, Zubair, Muhammad, Khan, Asad, Li, Yang, Shah, Basit, Zhao, Daren, Iqbal, Furhan, Jiang, Xiaohua, Guo, Tonghang, Xu, Peng, Xu, Bo, Wu, Limin, Ma, Hui, Zhang, Yuanwei, Zhang, Huan, Shi, Qinghua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362269/
https://www.ncbi.nlm.nih.gov/pubmed/37485353
http://dx.doi.org/10.1016/j.isci.2023.107193
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author Liu, Junyan
Rahim, Fazal
Zhou, Jianteng
Fan, Suixing
Jiang, Hanwei
Yu, Changping
Chen, Jing
Xu, Jianze
Yang, Gang
Shah, Wasim
Zubair, Muhammad
Khan, Asad
Li, Yang
Shah, Basit
Zhao, Daren
Iqbal, Furhan
Jiang, Xiaohua
Guo, Tonghang
Xu, Peng
Xu, Bo
Wu, Limin
Ma, Hui
Zhang, Yuanwei
Zhang, Huan
Shi, Qinghua
author_facet Liu, Junyan
Rahim, Fazal
Zhou, Jianteng
Fan, Suixing
Jiang, Hanwei
Yu, Changping
Chen, Jing
Xu, Jianze
Yang, Gang
Shah, Wasim
Zubair, Muhammad
Khan, Asad
Li, Yang
Shah, Basit
Zhao, Daren
Iqbal, Furhan
Jiang, Xiaohua
Guo, Tonghang
Xu, Peng
Xu, Bo
Wu, Limin
Ma, Hui
Zhang, Yuanwei
Zhang, Huan
Shi, Qinghua
author_sort Liu, Junyan
collection PubMed
description Azoospermia is a significant cause of male infertility, with non-obstructive azoospermia (NOA) being the most severe type of spermatogenic failure. NOA is mostly caused by congenital factors, but our understanding of its genetic causes is very limited. Here, we identified a frameshift variant (c.201_202insAC, p.Tyr68Thrfs∗17) and two nonsense variants (c.1897C>T, p.Gln633∗; c.2005C>T, p.Gln669∗) in KCTD19 (potassium channel tetramerization domain containing 19) from two unrelated infertile Chinese men and a consanguineous Pakistani family with three infertile brothers. Testicular histological analyses revealed meiotic metaphase I (MMI) arrest in the affected individuals. Mice modeling KCTD19 variants recapitulated the same MMI arrest phenotype due to severe disrupted individualization of MMI chromosomes. Further analysis showed a complete loss of KCTD19 protein in both Kctd19 mutant mouse testes and affected individual testes. Collectively, our findings demonstrate the pathogenicity of the identified KCTD19 variants and highlight an essential role of KCTD19 in MMI chromosome individualization.
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spelling pubmed-103622692023-07-23 Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans Liu, Junyan Rahim, Fazal Zhou, Jianteng Fan, Suixing Jiang, Hanwei Yu, Changping Chen, Jing Xu, Jianze Yang, Gang Shah, Wasim Zubair, Muhammad Khan, Asad Li, Yang Shah, Basit Zhao, Daren Iqbal, Furhan Jiang, Xiaohua Guo, Tonghang Xu, Peng Xu, Bo Wu, Limin Ma, Hui Zhang, Yuanwei Zhang, Huan Shi, Qinghua iScience Article Azoospermia is a significant cause of male infertility, with non-obstructive azoospermia (NOA) being the most severe type of spermatogenic failure. NOA is mostly caused by congenital factors, but our understanding of its genetic causes is very limited. Here, we identified a frameshift variant (c.201_202insAC, p.Tyr68Thrfs∗17) and two nonsense variants (c.1897C>T, p.Gln633∗; c.2005C>T, p.Gln669∗) in KCTD19 (potassium channel tetramerization domain containing 19) from two unrelated infertile Chinese men and a consanguineous Pakistani family with three infertile brothers. Testicular histological analyses revealed meiotic metaphase I (MMI) arrest in the affected individuals. Mice modeling KCTD19 variants recapitulated the same MMI arrest phenotype due to severe disrupted individualization of MMI chromosomes. Further analysis showed a complete loss of KCTD19 protein in both Kctd19 mutant mouse testes and affected individual testes. Collectively, our findings demonstrate the pathogenicity of the identified KCTD19 variants and highlight an essential role of KCTD19 in MMI chromosome individualization. Elsevier 2023-06-28 /pmc/articles/PMC10362269/ /pubmed/37485353 http://dx.doi.org/10.1016/j.isci.2023.107193 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Junyan
Rahim, Fazal
Zhou, Jianteng
Fan, Suixing
Jiang, Hanwei
Yu, Changping
Chen, Jing
Xu, Jianze
Yang, Gang
Shah, Wasim
Zubair, Muhammad
Khan, Asad
Li, Yang
Shah, Basit
Zhao, Daren
Iqbal, Furhan
Jiang, Xiaohua
Guo, Tonghang
Xu, Peng
Xu, Bo
Wu, Limin
Ma, Hui
Zhang, Yuanwei
Zhang, Huan
Shi, Qinghua
Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans
title Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans
title_full Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans
title_fullStr Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans
title_full_unstemmed Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans
title_short Loss-of-function variants in KCTD19 cause non-obstructive azoospermia in humans
title_sort loss-of-function variants in kctd19 cause non-obstructive azoospermia in humans
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362269/
https://www.ncbi.nlm.nih.gov/pubmed/37485353
http://dx.doi.org/10.1016/j.isci.2023.107193
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