Identification of CFAP52 as a novel diagnostic target of male infertility with defects of sperm head-tail connection and flagella development.

Abstract

Male infertility is a worldwide population health concern. Asthenoteratozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. No evidence indicates the relevance of <i>CFAP52</i> mutations to human male infertility. Our whole-exome sequencing identified compound heterozygous mutations in <i>CFAP52</i> recessively cosegregating with male infertility status in a non-consanguineous Chinese family. Spermatozoa of <i>CFAP52</i>-mutant patient mainly exhibited abnormal head-tail connection and deformed flagella. <i>Cfap52</i>-knockout mice resembled the human infertile phenotype, showing a mixed acephalic spermatozoa syndrome (ASS) and multiple morphological abnormalities of the sperm flagella (MMAF) phenotype. The ultrastructural analyses further revealed a failure of connecting piece formation and a serious disorder of '9+2' axoneme structure. CFAP52 interacts with a head-tail coupling regulator SPATA6 and is essential for its stability. Expression of microtubule inner proteins and radial spoke proteins were reduced after the CFAP52 deficiency. Moreover, CFAP52-associated male infertility in humans and mice could be overcome by intracytoplasmic sperm injection (ICSI). The study reveals a prominent role for CFAP52 in sperm development, suggesting that CFAP52 might be a novel diagnostic target for male infertility with defects of sperm head-tail connection and flagella development.