PT  - JOURNAL ARTICLE
AU  - Xiaojin He
AU  - Weiyu Li
AU  - Huan Wu
AU  - Mingrong Lv
AU  - Wangjie Liu
AU  - Chunyu Liu
AU  - Fuxi Zhu
AU  - Caihua Li
AU  - Youyan Fang
AU  - Chenyu Yang
AU  - Huiru Cheng
AU  - Junqiang Zhang
AU  - Jing Tan
AU  - Tingting Chen
AU  - Dongdong Tang
AU  - Bing Song
AU  - Xue Wang
AU  - Xiaomin Zha
AU  - Hongyan Wang
AU  - Zhaolian Wei
AU  - Shenmin Yang
AU  - Hexige Saiyin
AU  - Ping Zhou
AU  - Li Jin
AU  - Jian Wang
AU  - Zhiguo Zhang
AU  - Feng Zhang
AU  - Yunxia Cao
TI  - Novel homozygous <em>CFAP69</em> mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella
AID  - 10.1136/jmedgenet-2018-105486
DP  - 2019 Feb 01
TA  - Journal of Medical Genetics
PG  - 96--103
VI  - 56
IP  - 2
4099  - http://jmg.bmj.com/content/56/2/96.short
4100  - http://jmg.bmj.com/content/56/2/96.full
SO  - J Med Genet2019 Feb 01; 56
AB  - Background Male infertility is a major issue of human reproduction health. Asthenoteratospermia can impair sperm motility and cause male infertility. Asthenoteratospermia with multiple morphological abnormalities of the flagella (MMAF) presents abnormal spermatozoa with absent, bent, coiled, short and/or irregular-calibre flagella. Previous studies on MMAF reported that genetic defects in cilia-related genes (eg, AKAP4, DNAH1, CFAP43, CFAP44 and CFAP69) are the major cause of MMAF. However, the known MMAF-associated genes are only responsible for approximately 30% to 50% of human cases. We further investigated the cases with MMAF in search of additional genes mutated in this condition.Methods and results 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. Intriguingly, a homozygous frameshift mutation (p.Leu357Hisfs*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 case with homozygous nonsense mutation (p.Trp216*) 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 orthologue Cfap69 using the CRISPR-Cas9 technology. Remarkably, male Cfap69-knockout mice manifested with MMAF phenotypes.Conclusion Our experimental findings elucidate that homozygous loss-of-function mutations in CFAP69 can lead to asthenoteratospermia with MMAF in humans and mice.