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 sequen...

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Published in:Molecular genetics and genomics : MGG 2023-03, Vol.298 (2), p.353-360
Main Authors: Zhou, Xiaopei, Xi, Qingsong, Jia, Weimin, Li, Zhou, Liu, Zhenxing, Luo, Geng, Xing, Chenxi, Zhang, Dazhi, Hou, Meiqi, Liu, Huihui, Yang, Xue, Luo, Yalin, Peng, Xuejie, Wang, Guihua, Zou, Tingting, Zhu, Lixia, Jin, Lei, Zhang, Xianqin
Format: Article
Language:English
Subjects:
Amino acids
Animal Genetics and Genomics
Biochemistry
Biomedical and Life Sciences
Fertilization in Vitro
Genetic counseling
Genetic factors
Human Genetics
Humans
Immunofluorescence
In vitro fertilization
Infertility
Infertility, Male - genetics
Life Sciences
Localization
Male
Microbial Genetics and Genomics
Missense mutation
Mutants
Mutation
Original Article
Plant Genetics and Genomics
Public health
Random coil
Semen
Sperm Injections, Intracytoplasmic - methods
Theca
Transmission electron microscopy
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Summary: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 α‐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.
ISSN:1617-4615
1617-4623
DOI:10.1007/s00438-022-01985-0