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Biallelic mutations in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans and mice
Wensheng Liu1, Xiaoli Wei2,3, Xiaoyan Liu4
1Obstetrics and Gynecology Center, Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Background:
Asthenozoospermia is a major factor contributing to male infertility. The mitochondrial sheath (MS), an important organelle in the midpiece of spermatozoa, is crucial to sperm motility. ARMC12 is a mitochondrial peripheral membrane protein. Deletion of Armc12 impairs the arrangement of MS and causes infertility in mice. However, the role of ARMC12 in human asthenozoospermia remains unknown.
Objective:
To study the genetic defects in patients with asthenozoospermia.
Methods:
A total of 125 patients with asthenozoospermia and 120 men with proven fertility were recruited. Whole-exome sequencing and Sanger sequencing were performed for genetic analysis. Papanicolaou staining, HE staining, immunofluorescent staining, transmission electron microscopy and field emission scanning electron microscopy were employed to observe the morphological and structural defects of the spermatozoa and testes. Armc12-knockout mice were generated using the CRISPR-Cas9 system. Intracytoplasmic sperm injection was used to treat the patients.
Results:
Biallelic ARMC12 mutations were identified in three patients, including homozygous mutations in two siblings from a consanguineous family and compound heterozygous mutations in one sporadic patient. ARMC12 is mainly expressed in the midpiece of elongated and late spermatids in the human testis. The patients' spermatozoa displayed multiple midpiece defects, including absent MS and central pair, scattered or forked axoneme and incomplete plasma membrane. Spermatozoa from Armc12 mice showed parallel defects in the midpiece. Moreover, two patients were treated with intracytoplasmic sperm injection and achieved good outcomes.
Conclusion:
Our findings prove for the first time that defects in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans.
Insights
Genetic defects in ARMC12 cause asthenozoospermia and midpiece defects in human sperm. This study identifies ARMC12 mutations in infertile men and demonstrates their impact on sperm motility.
Area of Science:
- Reproductive biology
- Human genetics
- Spermatozoa morphology
Background:
- Asthenozoospermia is a primary cause of male infertility.
- The mitochondrial sheath (MS) in spermatozoa is vital for motility.
- ARMC12, a mitochondrial protein, is essential for MS structure and sperm function.
Purpose of the Study:
- Investigate the role of ARMC12 in human asthenozoospermia.
- Identify genetic defects associated with male infertility.
- Understand the structural basis of ARMC12-related infertility.
Main Methods:
- Whole-exome and Sanger sequencing in 125 asthenozoospermic patients and 120 fertile controls.
- Sperm and testis morphological analysis using microscopy techniques.
- Generation of Armc12-knockout mice for functional studies.
Main Results:
- Identified biallelic ARMC12 mutations in three patients with asthenozoospermia.
- Observed multiple midpiece defects in patient spermatozoa, including absent MS and axonemal abnormalities.
- Armc12-deficient mice exhibited similar sperm midpiece defects.
Conclusions:
- ARMC12 mutations are a novel cause of human asthenozoospermia.
- Defects in ARMC12 lead to structural abnormalities in the sperm midpiece.
- Intracytoplasmic sperm injection offers a potential treatment for ARMC12-related infertility.
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