Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human

Area of Science:

• Reproductive Biology
• Genetics
• Cell Biology

Background:

• Spermatogenesis defects lead to male infertility, affecting millions globally, with many cases remaining undiagnosed.
• Sperm flagella, crucial for motility, are complex structures containing the axoneme, a highly conserved microtubule-based apparatus.

Purpose of the Study:

• To investigate the genetic causes of primary infertility in men with multiple morphological abnormalities of the sperm flagella.
• To identify novel genes involved in sperm axoneme organization and function.

Main Methods:

• Whole-exome sequencing was performed on 78 infertile male patients.
• CRISPR/Cas9 gene editing was used to create CFAP43/44 homozygous mutant mice.
• Immunoelectron microscopy and stimulated-emission-depletion microscopy were employed on Trypanosoma brucei orthologs.

Main Results:

• Bi-allelic mutations in DNAH1, CFAP43, and CFAP44 were identified in 22 patients.
• Homozygous CFAP43/44 mutant mice exhibited infertility and severe flagellar defects.
• CFAP43 and CFAP44 proteins were localized between doublet microtubules and the paraflagellar rod in Trypanosoma brucei.

Conclusions:

• CFAP43 and CFAP44 are essential for functional flagella formation in both Trypanosoma and humans.
• These proteins share similar structures, unique axonemal localizations, and are critical for sperm motility.
• Mutations in CFAP43 and CFAP44 represent a significant cause of undiagnosed male infertility.