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

作　　者：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 FRay Lingbo Wang Xiaoyu Yang Feng Zhang Chunyu Liu 

机构地区：[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]UniversitéGrenoble Alpes,CNRS UMR 5309,INSERM U1209,Institute for Advanced Biosciences(IAB),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 Labof Reproduction Regulation,Shanghai Institute for Biomedical andPharmaceutical 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 Médicaleàla 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]State Key Laboratory of Reproductive Medicine and offspring health,Clinical Center for Reproductive Medicine,The First Affiliated Hospital of Nanjing Medical University,Nanjing 211166,Ch

出　　处：《Science China(Life Sciences)》2025年第3期777-792,共16页中国科学(生命科学英文版)

基　　金：supported by the National Natural Science Foundation of China(32288101,32100480,32370654,82271638,32322017);the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212200);Shanghai Hospital Development Center Foundation(SHDC12023121);the outstanding Youth Foundation of Hunan Provincial Natural Science Foundation of China(2023JJ20080).

摘　　要：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 asthenoteratozoospermia-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.

关 键 词：male infertility asthenoteratozoospermia MYCBPAP acrosome biogenesis MANCHETTE AXONEME 

分 类 号：R73[医药卫生—肿瘤]