A novel missense variant in CDK5RAP2 associated with non-obstructive azoospermia

Area of Science:

• Genetics
• Reproductive Biology
• Molecular Biology

Background:

• Non-obstructive azoospermia (NOA) is a severe male infertility cause, affecting 10-20% of azoospermic men.
• Spermatogenesis failure underlies NOA, prompting genetic research into causative factors.
• Dozens of genes linked to NOA have been identified, but novel mutations remain to be discovered.

Purpose of the Study:

• To identify a novel monogenic mutation responsible for non-obstructive azoospermia (NOA).

Main Methods:

• Family-based exome sequencing was performed on a consanguineous family with NOA.
• Segregation analysis, in silico protein modeling, and single-cell RNA sequencing were utilized.
• Bioinformatics and Sanger sequencing confirmed genetic findings.

Main Results:

• A rare homozygous missense variant (c.A4003T:p.R1335W) in the CDK5RAP2 gene was identified in NOA brothers.
• Protein modeling indicated the R1335W mutation disrupts the interaction site with EB1/MAPRE1.
• The mutation replaces a charged Arginine with a hydrophobic Tryptophan, potentially destabilizing CDK5RAP2 structure.

Conclusions:

• A novel CDK5RAP2 missense variant segregates with male infertility and NOA in a consanguineous family.
• In silico predictions suggest the CDK5RAP2 variant impairs centrosomic maturation during spermatogenesis.
• This highlights a potential new genetic cause for NOA and male infertility.