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

Junyan Liu; Fazal Rahim; Jianteng Zhou; Suixing Fan; Hanwei Jiang; Changping Yu; Jing Chen; Jianze Xu; Gang Yang; Wasim Shah; Muhammad Zubair; Asad Khan; Yang Li; Basit Shah; Daren Zhao; Furhan Iqbal; Xiaohua Jiang; Tonghang Guo; Peng Xu; Bo Xu; Limin Wu; Hui Ma; Yuanwei Zhang; Huan Zhang; Qinghua Shi

doi:10.1016/j.isci.2023.107193

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

iScience. 2023 Jun 28;26(7):107193. doi: 10.1016/j.isci.2023.107193. eCollection 2023 Jul 21.

Authors

Junyan Liu¹, Fazal Rahim¹, Jianteng Zhou¹, Suixing Fan¹, Hanwei Jiang¹, Changping Yu¹, Jing Chen¹, Jianze Xu¹, Gang Yang¹, Wasim Shah¹, Muhammad Zubair¹, Asad Khan¹, Yang Li¹, Basit Shah¹, Daren Zhao¹, Furhan Iqbal², Xiaohua Jiang¹, Tonghang Guo¹, Peng Xu³, Bo Xu¹, Limin Wu¹, Hui Ma¹, Yuanwei Zhang¹, Huan Zhang¹, Qinghua Shi¹

Affiliations

¹ Division of Reproduction and Genetics, First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, Institute of Health and Medicine, Hefei Comprehensive National Science Center, University of Science and Technology of China, Hefei 230027, China.
² Institute of Pure and Applied Biology, Zoology Division, Bahauddin Zakariya University, Multan 60800, Pakistan.
³ Hainan Jinghua Hejing Hospital for Reproductive Medicine, Hainan 570125, China.

Abstract

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.

Keywords: Biochemistry; biological sciences; health sciences.