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.

Genetic male infertility and mutation of CATSPER ion channels

“…The defects included nonmotile sperm or sperm motility below the normal threshold, low sperm count, increased abnormally structured spermatozoa and reduced semen volume. 15 The pH of the semen of both individuals was within the normal range.…”

“…23 However, involvement of this channel in human male fertility was only shown very recently in two consanguineous Iranian families. 15 In both families insertion mutations were identified in exon 1 (c. 539-540insT and c. 948-949insATGGC) that lead to frameshift Figure 1 Sperm motility defects due to loss of CATSPER channel. CATSPER proteins are expressed in the principal piece of the sperm flagellum (box).…”

“…21 The mutant CATSPER1 proteins predicted for the NSMI families lack all six transmembrane domains and the P-loop. 15 Thus, even if a truncated protein is made, it is predicted that CATSPER1 channel activity would be abolished in homozygous carriers of either of these mutations. Likewise, in DIS patients, part or all of the CATSPER2 gene is deleted, leading to predicted loss of the CATSPER2 protein.…”

“…Mutations affecting the sperm-specific CATSPER1 (OMIM 606389) and CATSPER2 (OMIM 607249) alkalinization-activated calcium channels, two of four members of the CATSPER family, have been associated with male infertility in mice and humans (Table 2; Figure 1). Although mutation of CATSPER1 has been associated with nonsyndromic male infertility (NSMI), 15 loss of CATPSER2 and STRC in contiguous gene deletion syndromes leads to deafness-infertility syndrome (DIS) (OMIM 611102) (Table 2). 16,17 In mice, genetic disruption of any one of the four sperm-specific CatSper channels (CatSper1/2/3/4) leads to male infertility by impairing sperm motility.…”

Flagellar ion channels of sperm: similarities and differences between species

“…Loss of any one member of the complex is detrimental to male fertility due to their interdependent protein expression in spermatozoa though CatSper␤ and CatSper␥ null mice have yet to be observed [9,19,22,24,49,74]. Humans with mutations within the CatSper1 or CatSper2 genes were also shown to be infertile revealing CatSper's importance as a general mechanism in mammalian fertility potential [6,[75][76][77][78][79][80]. By combining mouse genetics with sperm patch clamp method CatSper activity was eventually directly recorded in 2006 and CatSper was established as the principal Ca 2+ channel of mouse sperm [16].…”