Premium
Pathogenic variants of ATG4D in infertile men with non‐obstructive azoospermia identified using whole‐exome sequencing
Author(s) -
Sha Yanwei,
Liu Wensheng,
Wei Xiaoli,
Zhu Xingshen,
Tang Bowen,
Zhang Xiaoya,
Yang Xiaoyu,
Wang Yifeng,
Wang Xiong
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13995
Subject(s) - azoospermia , exome sequencing , biology , male infertility , compound heterozygosity , genetics , phenotype , gene , obstructive azoospermia , exome , infertility , pregnancy
Non‐obstructive azoospermia (NOA) is the most severe form of male infertility, and it is primarily associated with genetic defects. We performed whole‐exome sequencing of 236 patients with NOA and identified a homozygous pathogenic variant of autophagy‐related 4D cysteine peptidase (ATG4D) in two siblings from a consanguineous family and compound heterozygous pathogenic variants of ATG4D in two sporadic cases. The expression of LC3B, a regulator of autophagic activity, was significantly decreased, and the apoptosis rate of spermatogenic cells in testicular tissues was increased. Transfection of GC‐2spd cells with a ATG4D mutant plasmid (Flag‐Atg4d mut ) significantly decreased the expression level of Lc3b and increased the rate of apoptosis. Moreover, a pathogenic variant in X‐linked ATG4A and compound heterozygous pathogenic variants of ATG4B were identified in one patient each. All novel variants were segregated by disease phenotype and were predicted to be pathogenic. Our findings revealed that autophagy‐related cysteine peptidase family genes may play crucial roles in human spermatogenesis and identified ATG4D as a novel candidate gene for male infertility due to NOA.