Bi-allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice

Abstract

Male infertility is a major health concern. Among its different causes, multiple morphological abnormalities of the flagella (MMAF) induces asthenozoospermia and is one of the most severe forms of qualitative sperm defects. Sperm of affected men display short, coiled, absent, and/or irregular flagella. To date, six genes (DNAH1, CFAP43, CFAP44, CFAP69, FSIP2, and WDR66) have been found to be recurrently associated with MMAF, but more than half of the cases analyzed remain unresolved, suggesting that many yet-uncharacterized gene defects account for this phenotype. Here, whole-exome sequencing (WES) was performed on 168 infertile men who had a typical MMAF phenotype. Five unrelated affected individuals carried a homozygous deleterious mutation in ARMC2, a gene not previously linked to the MMAF phenotype. Using the CRISPR-Cas9 technique, we generated homozygous Armc2 mutant mice, which also presented an MMAF phenotype, thus confirming the involvement of ARMC2 in human MMAF. Immunostaining experiments in AMRC2-mutated individuals and mutant mice evidenced the absence of the axonemal central pair complex (CPC) proteins SPAG6 and SPEF2, whereas the other tested axonemal and peri-axonemal components were present, suggesting that ARMC2 is involved in CPC assembly and/or stability. Overall, we showed that bi-allelic mutations in ARMC2 cause male infertility in humans and mice by inducing a typical MMAF phenotype, indicating that this gene is necessary for sperm flagellum structure and assembly.

DNAH17 is associated with asthenozoospermia and multiple morphological abnormalities of sperm flagella

“…MMAF is an autosomal‐recessive disorder linked to mutations in several genes, including DNAH1 (Ben Khelifa et al., ; Wang et al., ), DNAH2 (Li et al., ), CFAP43 , and CFAP44 (Sha et al., ; Tang et al., ; Wu et al., ), CFAP69 (Dong et al., ; He et al., ), CFAP251 (also known as WDR66 ) (Kherraf et al., ; Li et al., ), FSIP2 (Martinez et al., ), ARMC2 (Coutton et al., ), AK7 ( Lores et al., ), QRICH2 (Shen et al., ), SPEF2 (Liu et al., ; Sha et al., ), TTC21A (Liu et al., ), and CEP135 (Sha et al., ). However, further research is needed to determine the genetic causes of the remaining 40%–50% of the MMAF patients (Liu et al., ).…”

Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations

“…The genetic characterization of this phenotype began in 2014 with the identification of DNAH1 (dynein axonemal heavy chain 1) as a major gene implicated in MMAF . After the development and the introduction of high throughput sequencing (HTS) techniques such as whole exome sequencing (WES), deleterious mutations were formally identified in eight additional MMAF genes ( AK7 , ARMC2 , CFAP43 , CFAP44 , CFAP69 , FSIP2 , TTC21A , and WDR66 ) showing the high genetic heterogeneity of this phenotype. Despite these important advances in gene identification, about half of the MMAF cases remain idiopathic without a genetic diagnosis.…”

Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype

“…Many researchers have shown that the MMAF phenotype is associated with genetic mutations. Previous studies revealed that mutations in DNAH1 (MIM: 603332), DNAH2 (MIM: 603333), AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), AK7 (MIM: 615364), CFAP251 (MIM: 618146), CEP135 (MIM: 611423), FSIP2 (MIM: 615796), ARMC2 (MIM: 611226), QRICH2 (MIM: 618304), SPEF2 (MIM: 610172), CFAP69 (MIM: 617949), CFAP43 (MIM: 617558) and CFAP44 (MIM:617559) could cause the human MMAF phenotype . However, more research is needed to reveal the etiology of the remaining 30%–40% of MMAF cases.…”