A novel homozygous mutation in ACTL7A leads to male infertility

Male infertility, a global public health problem, exhibits complex pathogenic causes and genetic factors deserve further discovery and study. We identified a novel homozygous missense mutation c.224A > C (p.D75A) in ACTL7A gene in two infertile brothers with teratozoospermia by whole-exome sequencing (WES). In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) showed fertilization failure of the two affected couples. The three-dimensional (3D) models showed that a small section of alpha-helix transformed into random coil in the mutant ACTL7A protein and mutant amino acid lacked a hydrogen bond with Ser170 amino acid. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. Furthermore, ACTL7A mutation caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients, which may be the key reasons for the fertilization failure after ICSI. Our findings expand the spectrum of ACTL7A mutations and provide novel theoretical basis for genetic counseling.

Automated summary

Male infertility is a global public health problem with complex pathogenic causes. Through whole-exome sequencing, we identified a novel homozygous missense mutation in the ACTL7A gene in two infertile brothers with teratozoospermia. In vitro fertilization and intracytoplasmic sperm injection showed fertilization failure, and further analysis revealed irregular perinuclear theca (PT) and acrosomal ultrastructural defects in the sperm of these patients. The mutation also caused abnormal localization and reduced expression of PLCZ1, which may contribute to the fertilization failure. This study expands the understanding of ACTL7A mutations and provides a basis for genetic counseling.