A novel stop-gain mutation in ARMC2 is associated with multiple morphological abnormalities of the sperm flagella
Ihsan Khan1, Sobia Dil1, Huan Zhang1
1First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.
Research Question:
Male infertility is a global issue worldwide and multiple morphological abnormalities of the sperm flagella (MMAF) is one of the most severe forms of the qualitative sperm defects with a heterogeneous genetic cause that has not been completely understood. Can whole-exome sequencing (WES) reveal novel genetic causes contributing to MMAF in a consanguineous Pakistani family, comprising three infertile brothers?
Design:
WES and bioinformatic analysis were conducted to screen potential pathogenic variants. The identified variant was validated by Sanger sequencing in all available family members Transmission electron microscopy analyses was carried out to examine the flagella ultrastructure of spermatozoa from patient.
Results:
WES and Sanger sequencing identified a novel homozygous stop-gain mutation (ENST00000392644.4, c.182C>G, p.S61X) in ARMC2, which is expected to lead to loss of protein functions. Transmission electron microscopy analyses revealed that the flagellar ultrastructure of the patient's spermatozoa was disorganized along with a complete absence of central pair complex (CPC), suggesting that ARMC2 is involved in the assembly, stability of the axonemal complex, or both, particularly the CPC.
Conclusion:
We report that a familial stop-gain mutation in ARMC2 is associated with male infertility in humans caused by MMAF accompanied with loss of CPCs and axonemal disorganization. We provide genetic evidence that ARMC2 is essential for human spermatogenesis and its mutation may be pathogenic for MMAF. These findings will improve the knowledge about the genetic basis of MMAF and provide information for genetic counselling of this disease.
Insights
A novel ARMC2 gene mutation causes male infertility in a Pakistani family by disrupting sperm flagella structure and central pair complex assembly. This finding highlights ARMC2's essential role in human spermatogenesis and MMAF pathogenesis.
Area of Science:
- Genetics
- Reproductive Biology
- Cell Biology
Background:
- Male infertility affects millions globally, with multiple morphological abnormalities of the sperm flagella (MMAF) representing a severe qualitative sperm defect.
- The genetic underpinnings of MMAF are complex and not fully elucidated, necessitating further research into novel causative factors.
Observation:
- Whole-exome sequencing (WES) was employed to investigate a consanguineous Pakistani family with three affected brothers exhibiting male infertility.
- A novel homozygous stop-gain mutation (c.182C>G, p.S61X) in the ARMC2 gene was identified in affected individuals.
- Transmission electron microscopy revealed disorganization of sperm flagella ultrastructure and a complete absence of the central pair complex (CPC) in patients.
Findings:
- The identified ARMC2 mutation is predicted to result in loss of protein function.
- ARMC2 plays a critical role in the assembly and/or stability of the axonemal complex, particularly the central pair complex (CPC).
- This study provides genetic evidence linking ARMC2 mutations to male infertility in humans due to MMAF with CPC loss and axonemal disorganization.
Implications:
- The findings expand our understanding of the genetic basis of male infertility and MMAF.
- Identifying ARMC2 as a gene essential for human spermatogenesis offers new insights into reproductive health.
- This research provides valuable information for genetic counseling and potential diagnostic approaches for families affected by MMAF.
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