Mutations in CCIN cause teratozoospermia and male infertility  

CCIN突变引起畸形精子症和男性不育

作　　者：Yong Fan Chenhui Huang Juan Chen Yanyan Chen Yan Wang Zhiguang Yan Weina Yu Haibo Wu Ying Yang Leitong Nie Sijia Huang Fangfang Wang Haoyu Wang Yunfeng Hua Qifeng Lyu Yanping Kuang Ming Lei 凡永;黄晨辉;陈娟;陈艳艳;王妍;燕志光;于韦娜;吴海波;杨颖;聂雷同;黄思佳;王方方;王皓煜;华云峰;吕祁峰;匡延平;雷鸣(Department of Assisted Reproduction,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China;Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China;Shanghai Institute of Precision Medicine,Shanghai 200125,China;National Key Laboratory of Crop Genetic Improvement,Huazhong Agriculture University,Wuhan 430072,China;State Key Laboratory of Oncogenes and Related Genes,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China;Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China)

机构地区：[1]Department of Assisted Reproduction,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [2]Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [3]Shanghai Institute of Precision Medicine,Shanghai 200125,China [4]National Key Laboratory of Crop Genetic Improvement,Huazhong Agriculture University,Wuhan 430072,China [5]State Key Laboratory of Oncogenes and Related Genes,Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [6]Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

出　　处：《Science Bulletin》2022年第20期2112-2123,M0004,共13页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(31930063,81771533,81901531,31971137,and 81871163);the National Key Research and Development Program of China(2018YFC2000102,2018YFA0107004,and 2018YFC1003000);the Shanghai Municipal Health Commission and Collaborative Innovation Cluster Project(2019CXJQ01);SHIPM-pi Fund(JY201801);SHIPM-mu Fund(JC201802)。

摘　　要：Teratozoospermia is usually associated with defective spermiogenesis and is a disorder with considerable genetic heterogeneity. Although previous studies have identified several teratozoospermia-associated genes, the etiology remains unknown for a majority of affected men. Here, we identified a homozygous missense mutation and a compound heterozygous mutation of CCIN in patients suffering from teratozoospermia. CCIN encodes the cytoskeletal protein Calicin that is involved in the formation and maintenance of the highly regular organization of the calyx of mammalian spermatozoa, and has been proposed to play a role in sperm head structure remodeling during the process of spermiogenesis. Our morphological and ultrastructural analyses of the spermatozoa obtained from all three men harboring deleterious CCIN mutants reveal severe head malformation. Further immunofluorescence assays unveil markedly reduced levels of Calicin in spermatozoa. These patient phenotypes are successfully recapitulated in mouse models expressing the disease-associated variants, confirming the role of Calicin in male fertility.Notably, all mutant spermatozoa from mice and human patients fail to adhere to the zona mass, which likely is the major mechanistic reason for CCIN-mutant sperm-derived infertility. Finally, the use of intracytoplasmic sperm injections(ICSI) successfully makes mutated mice and two couples with CCIN variants have healthy offspring. Taken together, our findings identify the role of Calicin in sperm head shaping and male fertility, providing important guidance for genetic counseling and assisted reproduction treatments.畸形精子症通常与精子变形缺陷相关,具有遗传异质性.之前的研究确定了一些致病基因,但大多数畸形精子症的病因仍然未知.该研究在畸形精子症患者中鉴定出CCIN^(H42L/H42L)和CCIN^(R432W/C447*)突变. CCIN编码细胞骨架蛋白Calicin,参与哺乳动物精子花萼结构的形成和维持,被推测在精子头部重塑过程中发挥作用.对携带上述CCIN突变位点的患者精子进行的形态学分析显示精子头部严重畸形.进一步的研究表明CCIN突变精子的Calicin蛋白显著降低.携带与患者相同突变位点的小鼠模型成功地再现了患者的不育表型.来自患者和突变小鼠的精子都无法黏附到卵子的透明带,这可能是CCIN突变导致雄性不育的主要原因.使用卵胞浆内单精子注射可以成功地克服这一缺陷,使患者及突变体小鼠获得子代.综上所述,该研究确定了Calicin在精子头部变形和男性生育中的功能,为遗传咨询和辅助生殖治疗提供了重要指导.

关 键 词：CCIN TERATOZOOSPERMIA Male infertility The calyx Whole-exome sequencing Mouse model 

分 类 号：R698.2[医药卫生—泌尿科学]