Homozygous mutations in CFAP69 cause male infertility with multiple morphological abnormalities of the sperm flagella
作者单位：Reproductive Medicine CenterDepartment of Obstetrics and GynecologyThe First Affiliated Hospital of Anhui Medical University Anhui Province Key Laboratory of Reproductive Health and GeneticsAnhui Medical University Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs Obstetrics and Gynecology HospitalState Key Laboratory of Genetic Engineering at School of Life SciencesInstitute of Reproduction and DevelopmentFudan University Key Laboratory of Reproduction Regulation of NHFPCCollaborative Innovation Center of Genetics and DevelopmentFudan University Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases Genesky Biotechnologies Inc Center of Cryo-Electron MicroscopyZhejiang University Department of PathologyAnhui Medical University Center for Reproduction and GeneticsSuzhou Hospital affiliated to Nanjing Medical University Department of Medical Genetics and Molecular Diagnostic LaboratoryShanghai Children’s Medical CenterShanghai Jiaotong University School of Medicine
会议名称：《第十一届全国遗传病诊断与产前诊断学术交流会暨第二届海峡两岸医药卫生交流协会遗传与生殖专业委员会年会》
会议日期：2018年
学科分类：100208[医学-临床检验诊断学] 1002[医学-临床医学] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学]
关 键 词：CFAP69 flagella knockout mice male infertility sequencing sperm
摘 要：Purpose: Male infertility is a major issue of human reproduction ***-teratospermia can impair sperm motility and cause male infertility. Male individuals with multiple morphological abnormalities of the flagella(MMAF)present abnormal spermatozoa with absent, bent, coiled, short and/or irregular-caliber flagella. Previous studies on MMAF reported that genetic defects in cilia-related genes(e.g. DNAH1 and CCDC39) are the major cause of MMAF. However, the known MMAF-associated genes are only responsible for approximately half of human cases. Pathogenic mechanisms still remain to be elucidated in ***: We conducted whole-exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family. Sanger sequencing was also conducted in additional individuals with MMAF. Furthermore, we generated the knockout model using the CRISPR-Cas9 ***: Intriguingly, a homozygous frameshift mutation(***357 Hisfs*11) was identified in the gene encoding CFAP69(cilia and flagella associated protein 69),which is highly expressed in testis. The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a homozygous nonsense mutation(***216*) of CFAP69. Both of these CFAP69 loss-of-function mutations were not present in the human population genome data archived in the 1000 Genomes Project and ExAC databases, nor in 875 individuals of two Han Chinese control populations. Furthermore, we generated the knockout model in mouse ortholog Cfap69. Remarkably, male Cfap69-knockout mice manifested with MMAF ***: Our experimental findings elucidate that homozygous loss-of-function mutations in CFAP69 can lead to male infertility with MMAF in humans and mice.