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Flow Cytometric Analysis of Biomarkers for Detecting Human Sperm Functional Defects
Published on: April 21, 2022
Identification of DNAH6 mutations in infertile men with multiple morphological abnormalities of the sperm flagella
Chaofeng Tu1,2,3, Hongchuan Nie1,2,3, Lanlan Meng2
1Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, 410078, China.
Abstract:
Male infertility due to spermatogenesis defects affects millions of men worldwide. However, the genetic etiology of the vast majority remains unclear. Here we describe three men with primary infertility due to multiple morphological abnormalities of the sperm flagella (MMAF) from two unrelated Han Chinese families. We performed whole-exome sequencing (WES) and Sanger sequencing on the proband of family 1, and found that he carried novel compound heterozygous missense mutations in dynein axonemal heavy chain 6 (DNAH6) that resulted in the substitution of a conserved amino acid residue and co-segregated with the MMAF phenotype in this family. Papanicolaou staining and transmission electron microscopy analysis revealed morphological and ultrastructural abnormalities in the sperm flagella in carriers of these genetic variants. Immunostaining experiments showed that DNAH6 was localized in the sperm tail. This is the first report identifying novel recessive mutations in DNAH6 as a cause of MMAF. These findings expand the spectrum of known MMAF mutations and phenotypes and provide information that can be useful for genetic and reproductive counseling of MMAF patients.
Insights
Novel mutations in the DNAH6 gene are identified as a cause of multiple morphological abnormalities of the sperm flagella (MMAF) in men. This discovery aids in understanding male infertility and provides insights for genetic counseling.
Area of Science:
- Human Genetics
- Reproductive Biology
- Molecular Medicine
Background:
- Male infertility impacts millions globally, with unclear genetic causes for most cases.
- Spermatogenesis defects are a significant contributor to male infertility.
- Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare cause of primary infertility.
Purpose of the Study:
- To investigate the genetic basis of primary infertility in three men with MMAF from two unrelated families.
- To identify novel genetic variants associated with MMAF phenotype.
- To elucidate the role of DNAH6 in sperm flagellar structure and function.
Main Methods:
- Whole-exome sequencing (WES) and Sanger sequencing were performed on affected individuals.
- Papanicolaou staining and transmission electron microscopy (TEM) were used to analyze sperm flagellar morphology.
- Immunostaining experiments localized DNAH6 protein within sperm tails.
Main Results:
- Novel compound heterozygous missense mutations in the dynein axonemal heavy chain 6 (DNAH6) gene were identified in affected individuals.
- These DNAH6 mutations co-segregated with the MMAF phenotype within the studied families.
- Sperm flagella exhibited morphological and ultrastructural abnormalities in carriers of the identified DNAH6 variants.
Conclusions:
- This study reports the first identification of recessive DNAH6 mutations causing MMAF.
- The findings expand the known spectrum of genetic causes for MMAF.
- These results are valuable for genetic and reproductive counseling for patients with MMAF.
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