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

Taiwan J Obstet Gynecol. 2023 Nov;62(6):830-837. doi: 10.1016/j.tjog.2023.03.015.

Abstract

Objective: The most severe type of male infertility is non-obstructive azoospermia (NOA), where there is no sperm in the ejaculate due to failure of spermatogenesis, affecting 10%-20% of infertile men with azoospermia. Genetic studies have identified dozens of NOA genes. The main aim of the present study is to identify a novel monogenic mutation that may cause NOA.

Materials and methods: We studied the pedigree of a consanguineous family with three NOA and one fertile brother by a family-based exome-sequencing, segregation analysis, insilico protein modeling and single-cell RNA sequencing data analysis.

Results: Bioinformatics analysis followed by sanger sequencing revealed that three NOA brothers were homozygous for a rare missense variant in Cyclin Dependent Kinase Regulatory Subunit Associated Protein 2 (Centrosomin) CDK5RAP2 (NM_018249:exon26:c.A4003T:p.R1335W, rs761196443). Protein modeling demonstrated that CDK5RAP2, Arg1335Trp resided nearby the Microtubule Associated Protein RP/EB Family Member 1 (EB1/MAPRE1) interaction site. As a consequence of the R1335W mutation, the positively charged Arginine was replaced by to the hydrophobic tryptophan residue, possibly leading to local instability in the structure and perturbation in the CDK5RAP2-MAPRE1 interaction.

Conclusion: Our study reports a novel missense variant of CDK5RAP2 that segregates in homozygosity with male infertility and NOA in a consanguineous family. In silico structural predictions and gene expression data indicate a potential role of the CDK5RAP2 variant in causing defective centrosomic maturation during spermatogenesis.

Keywords: Centrosomine; EB1/MAPRE1; Spermatogenesis; Spindle checkpoint; WES.

MeSH terms

  • Azoospermia* / complications
  • Azoospermia* / genetics
  • Cell Cycle Proteins / genetics
  • Humans
  • Infertility, Male* / genetics
  • Male
  • Mutation
  • Mutation, Missense
  • Nerve Tissue Proteins / genetics

Substances

  • CDK5RAP2 protein, human
  • Nerve Tissue Proteins
  • Cell Cycle Proteins

Supplementary concepts

  • Azoospermia, Nonobstructive