Mutations in PMFBP1 Cause Acephalic Spermatozoa Syndrome

Am J Hum Genet. 2018 Aug 2;103(2):188-199. doi: 10.1016/j.ajhg.2018.06.010.

Fuxi Zhu ¹, Chao Liu ², Fengsong Wang ³, Xiaoyu Yang ⁴, Jingjing Zhang ¹, Huan Wu ¹, Zhiguo Zhang ⁵, Xiaojin He ⁵, Zhou Zhang ¹, Ping Zhou ⁵, Zhaolian Wei ⁵, Yongliang Shang ², Lina Wang ², Ruidan Zhang ², Ying-Chun Ouyang ², Qing-Yuan Sun ², Yunxia Cao ⁶, Wei Li ⁷

Affiliations

1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China.
2 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
3 School of Life Science, Anhui Medical University, Hefei 230022, China.
4 State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
5 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China.
6 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China. Electronic address: caoyunxia6@126.com.
7 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: leways@ioz.ac.cn.

PMID: 30032984 DOI: 10.1016/j.ajhg.2018.06.010

Abstract

Acephalic spermatozoa syndrome is a severe teratozoospermia that leads to male infertility. Our previous work showed that biallelic SUN5 mutations are responsible for acephalic spermatozoa syndrome in about half of affected individuals, while pathogenic mechanisms in the other individuals remain to be elucidated. Here, we identified a homozygous nonsense mutation in the testis-specific gene PMFBP1 using whole-exome Sequencing in a consanguineous family with two infertile brothers with acephalic spermatozoa syndrome. Sanger Sequencing of PMFBP1 in ten additional infertile men with acephalic spermatozoa syndrome and without SUN5 mutations revealed two homozygous variants and one compound heterozygous variant. The disruption of Pmfbp1 in male mice led to infertility due to the production of acephalic spermatozoa and the disruption of PMFBP1's cooperation with SUN5 and SPATA6, which plays a role in connecting sperm head to the tail. PMFBP1 mutation-associated male infertility could be successfully overcome by intracytoplasmic sperm injection (ICSI) in both mouse and human. Thus, mutations in PMFBP1 are an important cause of infertility in men with acephalic spermatozoa syndrome.

Keywords

ICSI; PMFBP1; acephalic spermatozoa syndrome; head-tail coupling apparatus; male infertility.

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