Homozygous deleterious variants in MYCBPAP induce asthenoteratozoospermia involving abnormal acrosome biogenesis, manchette structure and sperm tail assembly in humans and mice

Yiling Zhou; Chaofeng Tu; Charles Coutton; Jianan Tang; Shixiong Tian; Shuyan Tang; Guillaume Martinez; Dapeng Zhou; Célia Tebbakh; Jiaxiong Wang; Raoudha Zouari; Xuehai Zhou; Selima Fourati Ben Mustapha; Xuemei Wang; Bangguo Wu; Xinyan Geng; Shuang Liu; Li Jin; Huijuan Shi; Yue-Qiu Tan; Pierre F Ray; Lingbo Wang; Xiaoyu Yang; Feng Zhang; Chunyu Liu

doi:10.1007/s11427-024-2757-7

Homozygous deleterious variants in MYCBPAP induce asthenoteratozoospermia involving abnormal acrosome biogenesis, manchette structure and sperm tail assembly in humans and mice

Sci China Life Sci. 2024 Dec 18. doi: 10.1007/s11427-024-2757-7. Online ahead of print.

Authors

Yiling Zhou^#¹, Chaofeng Tu^#^{2

3}, Charles Coutton^#^{4

5}, Jianan Tang^#⁶, Shixiong Tian^#⁷, Shuyan Tang¹, Guillaume Martinez^{4

5}, Dapeng Zhou¹, Célia Tebbakh^{4

5}, Jiaxiong Wang^{8

9}, Raoudha Zouari¹⁰, Xuehai Zhou¹¹, Selima Fourati Ben Mustapha¹⁰, Xuemei Wang⁶, Bangguo Wu⁷, Xinyan Geng¹², Shuang Liu¹, Li Jin¹, Huijuan Shi⁶, Yue-Qiu Tan^{2

3}, Pierre F Ray^{4

13}, Lingbo Wang^{14

15}, Xiaoyu Yang¹⁶, Feng Zhang^{17

18

19}, Chunyu Liu^{20

21}

Affiliations

¹ Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, 200011, China.
² Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China.
³ Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha, 410008, China.
⁴ Institute for Advanced Biosciences (IAB), Université Grenoble Alpes, CNRS UMR 5309, INSERM U1209, Site Santé-Allée des Alpes, La Tronche, 38700, France.
⁵ CHU Grenoble Alpes, Hôpital Couple-Enfant, UM de Génétique Chromosomique, Grenoble, 38000, France.
⁶ Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, 200237, China.
⁷ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
⁸ State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, China.
⁹ Suzhou Municipal Hospital, Suzhou, 215002, China.
¹⁰ Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, 1003, Tunisia.
¹¹ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
¹² Soong Ching Ling Institute of Maternity and Child Health, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
¹³ CHU Grenoble Alpes, UM GI-DPI, Grenoble, 38000, France.
¹⁴ Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, 200011, China. [email protected].
¹⁵ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China. [email protected].
¹⁶ State Key Laboratory of Reproductive Medicine and offspring health, Clinical Center for Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China. [email protected].
¹⁷ Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Institute of Medical Genetics and Genomics, Fudan University, Shanghai, 200011, China. [email protected].
¹⁸ Soong Ching Ling Institute of Maternity and Child Health, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. [email protected].
¹⁹ Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China. [email protected].
²⁰ Soong Ching Ling Institute of Maternity and Child Health, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. [email protected].
²¹ Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China. [email protected].

^# Contributed equally.

PMID: 39704931
DOI: 10.1007/s11427-024-2757-7

Abstract

Asthenoteratozoospermia is a common cause of male infertility. To further define the genetic causes underlying asthenoteratozoospermia, we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases. Replication analyses in a French cohort revealed an additional asthenoter-atozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP. All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases. Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases. Subsequently, we generated a Mycbpap knockout (Mycbpap^-/-) mouse model, which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella. Further investigations demonstrated that Mycbpap^-/- male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis. Intriguingly, proteomic analyses indicated that the proteins related to spermatogenesis, acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap^-/- male mice. Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70. Furthermore, MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections. Collectively, these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia. Our study will provide effective guidance for genetic counseling, clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility.

Keywords: MYCBPAP; acrosome biogenesis; asthenoteratozoospermia; axoneme; male infertility; manchette.