Human male infertility caused by mutations in the CATSPER1 channel protein

Abstract

Male infertility, a common barrier that prevents successful conception, is a reproductive difficulty affecting 15% of couples. Heritable forms of nonsyndromic male infertility can arise from single-gene defects as well as chromosomal abnormalities. Although no CATSPER gene has been identified as causative for human male infertility, male mice deficient for members of the CatSper gene family are infertile. In this study, we used routine semen analysis to identify two consanguineous Iranian families segregating autosomal-recessive male infertility. Autozygosity by descent was demonstrated in both families for a approximately 11 cM region on chromosome 11q13.1, flanked by markers D11S1765 and D11S4139. This region contains the human CATSPER1 gene. Denaturing high-performance liquid chromatography (DHPLC) and bidirectional sequence analysis of CATSPER1 in affected family members revealed two separate insertion mutations (c.539-540insT and c.948-949insATGGC) that are predicted to lead to frameshifts and premature stop codons (p.Lys180LysfsX8 and p.Asp317MetfsX18). CATSPER1 is one of four members of the sperm-specific CATSPER voltage-gated calcium channel family known to be essential for normal male fertility in mice. These results suggest that CATSPER1 is also essential for normal male fertility in humans.

Figure 1

Linkage Mapping of an Infertility Locus Shared by Two Iranian Families Genotyping of STRPs and a SNP on chromosome 11 in (A) family L-1025 and (B) family L-968. The region of autozygosity by descent, which includes CATSPER1, is boxed.

Figure 2

Genetic Analyses of Affected Family Members Reveals CATSPER1 Mutations Segregating with Infertility Insertion mutations were identified in exon 1 of CATSPER1 in both families. (A) Family L-1025 segregates a c.539-540insT mutation, family L-968 a c.948-949insATGGC mutation. Sequences were aligned to the human CATSPER1 cDNA sequence (uc001ogt.1; NM_053054). The forward DNA strand and CATSPER1 genotypes for screened family members are shown.

Figure 3

Predicted Effect of the Mutations on the CATSPER1 Protein The predicted alterations of CATSPER1 are severely truncated proteins if the transcripts are not subject to NMD ([A] family L-1025, [B] family L-968). Forward and reverse DNA strands, as well as the corresponding amino acid sequence, are shown.

Figure 4

The Role of CatSper1 in Capacitation and Fertilization Murine studies have shown that CatSper1 is essential for normal capacitation and fertilization. (A) CatSper1 expression in the mouse sperm tail. (B) CatSper1 null sperm cannot penetrate the zona pellucida to fertilize the oocyte.