HGNC Approved Gene Symbol: CATSPER2
Cytogenetic location: 15q15.3 Genomic coordinates (GRCh38) : 15:43,628,503-43,648,884 (from NCBI)
CATSPER is a sperm-specific ion channel that mediates calcium entry into sperm and is essential for sperm hyperactivated motility and male fertility. The CATSPER complex contains 4 pore-forming subunits, CATSPER1 (606389), CATSPER2, CATSPER3 (609120), and CATSPER4 (609121), and at least 2 auxiliary proteins, CATSPERB (611169) and CATSPERG (613452). Each pore-forming subunit has 6 transmembrane-spanning domains and an intracellular C-terminal coiled-coil domain. In addition, CATSPER1 has an intracellular N-terminal histidine-rich region. Both the pore-forming subunits and the auxiliary subunits of CATSPER localize to the sperm principal piece (review by Ren and Xia, 2010).
Quill et al. (2001) cloned a full-length cDNA encoding mouse Catsper2. The deduced 588-amino acid protein contains 6 transmembrane segments, which have characteristics of a voltage-gated ion channel, and a C-terminal cytoplasmic portion, which has possible tyrosine phosphorylation sites and an unconventional leucine zipper motif. Northern blot and PCR analyses of mouse tissues detected a 2.1-kb transcript expressed only in testis. In situ hybridization revealed Catsper2 expression limited to meiotic and postmeiotic cells. Western blot analysis showed a protein with an apparent molecular mass of 68 kD, and immunofluorescent localization showed staining of the flagellum of mouse cauda epididymal spermatozoa.
Using the mouse Catsper2 sequence as probe, Quill et al. (2001) cloned 3 similar cDNA sequences from human testis that appeared to be transcribed from a single gene. Two of the clones encode predicted proteins of 528 and 530 amino acids, designated CATSPER2A and CATSPER2B, respectively, that differ only by 2 tandem serines following the transmembrane region. The third clone contains a gap in the cDNA sequence that causes a frameshift and early termination, resulting in a 414-amino acid protein, designated CATSPER2C. The 3 human CATSPER2 proteins share 63 to 67% identity with mouse Catsper2. Northern blot analysis revealed a 2.1-kb CATSPER2 transcript expressed only in testis.
By FISH, Quill et al. (2001) mapped the mouse Catsper2 gene to chromosome 2E5-F1. They mapped the human CATSPER2 gene to chromosome 15q13, a region syntenic to mouse chromosome 2E5-F1, and identified a second gene in this region highly homologous to mouse Catsper2.
Avidan et al. (2003) mapped the CATSPER2 gene to a region of chromosome 15q15.1-q15.3 that shows a tandem duplication. The duplicated region contains a CATSPER2 pseudogene.
Smith et al. (2013) analyzed ionic currents in spermatozoa from an infertile French man with severe asthenoteratozoospermia and abnormal motility patterns, who was 1 (patient II-4) of 3 brothers previously studied by Avidan et al. (2003) and found to have a deletion in the CATSPER2 gene (see CYTOGENETICS). Patient spermatozoa lacked an initial CatSper current and failed to respond to progesterone at a range of concentrations, in contrast to spermatozoa from a fertile donor. Immunostaining revealed that the patient's sperm also lacked the CatSper-beta subunit (CATSPERB; 611169). The authors concluded that CatSper is the principal Ca(2+) channel of human spermatozoa and is strongly potentiated by progesterone. In addition, recording CatSper currents from human epididymal and testicular spermatozoa showed that CatSper sensitivity to progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated, consistent with an important role for the CatSper channel in human sperm nongenomic progesterone signaling. These results also demonstrated that the molecular mechanism responsible for activation of CatSper by progesterone arises early in sperm development, concurrently with the CatSper channel itself.
Dgany et al. (2002) reported a French family in which a 56-year-old male and his 2 brothers suffered from type I congenital dyserythropoietic anemia (CDA) (224120), asthenoteratozoospermia, and nonsyndromic deafness. They identified homozygosity for a point mutation within the codanin gene (N598S; 607465.0003) as the cause of the type I CDA. Avidan et al. (2003) found that the 3 sibs were also homozygous for an approximately 70-kb deletion in chromosome 15q15, which removed the entire stereocilin gene (STRC; 606440) and the last 2 exons (225 bp) of the CATSPER2 gene. Avidan et al. (2003) suggested that lack of functional stereocilin, which is mutated in nonsyndromic sensorineural deafness (DFNB16; 603720), and CATSPER2, a voltage-gated cation channel expressed exclusively in spermatozoa, may explain the observed deafness and male infertility phenotypes, respectively.
In 3 consanguineous Iranian families segregating nonsyndromic deafness and male infertility (611102), Zhang et al. (2007) identified an approximately 100-kb deleted region on chromosome 15q15.3 involving KIAA0377 (610979), CKMT1B (123290), STRC, and CATSPER2. The families did not have identical deletions, and haplotype analysis indicated that the families did not share a common ancestor. Zhang et al. (2007) noted that a large tandem repeat on chromosome 15q15.3 makes it prone to rearrangement.
In a cohort of 120 infertile Chinese men with normal semen parameters, Luo et al. (2019) performed patch-clamp recording of spermatozoa and identified a 24-year-old man (patient LYX-IMI-B) with complete disruption of the CatSper current but a normal potassium current and pH in his spermatozoa. Genome analysis revealed heterozygosity for a de novo deletion on chromosome 15 (chr15:43,894,500-43,950,000; GRCh37.p13) containing the entire CATSPER2 gene and 80% of the STRC (606440) gene. The patient had normal hearing. Patient spermatozoa showed only 8% of CATSPER2 transcripts and 5% of CATSPER2 protein compared to controls. Noting that approximately 1% of the male population carries a heterozygous deletion of CATSPER2 and is asymptomatic, the authors suggested that an intronic SNP (rs12443102) identified within the CATSPER2 gene on the nondeleted allele might be responsible for the low activity level. The patient's spermatozoa showed impaired penetration ability, deficient hyperactivation, and did not respond to progesterone. The authors concluded that the pore-forming subunit of CatSper is not involved in spermatogenesis but is essential for the sperm's ability to pass through the viscous female reproductive tract. The patient and his wife achieved singleton pregnancy using intracytoplasmic sperm injection.
Quill et al. (2003) generated Catsper2 -/- mice and found that males but not females were completely infertile. There was no change in sperm production, protein tyrosine phosphorylation that is associated with capacitation, induction of the acrosome reaction, forward velocity, or percentage of motility. However, the null sperm cells failed to acquire hyperactivated motility, which seems to render spermatozoa incapable of generating the 'power' needed for penetration of the extracellular matrix of the egg. In high viscosity medium, Catsper2 null spermatozoa lost the ability to swim forward, whereas wildtype cells did not. Quill et al. (2003) concluded that CATSPER2 is responsible for driving hyperactivated motility and that even with typical sperm forward velocities, fertilization is not possible in the absence of this highly active form of motility.
Avidan, N., Tamary, H., Dgany, O., Cattan, D., Pariente, A., Thulliez, M., Borot, N., Moati, L., Barthelme, A., Shalmon, L., Krasnov, T., Ben-Asher, E., and 9 others. CATSPER2, a human autosomal nonsyndromic male infertility gene. Europ. J. Hum. Genet. 11: 497-502, 2003. [PubMed: 12825070] [Full Text: https://doi.org/10.1038/sj.ejhg.5200991]
Dgany, O., Avidan, N., Delaunay, J., Krasnov, T., Shalmon, L., Shalev, H., Eidelitz-Markus, T., Kapelushnik, J., Cattan, D., Pariente, A., Tulliez, M., Cretien, A., and 13 others. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am. J. Hum. Genet. 71: 1467-1474, 2002. [PubMed: 12434312] [Full Text: https://doi.org/10.1086/344781]
Luo, T., Chen, H., Zou, Q., Wang, T., Cheng, Y., Wang, H., Wang, F., Jin, Z., Chen, Y., Weng, S., Zeng, X. A novel copy number variation in CATSPER2 causes idiopathic male infertility with normal semen parameters. Hum. Reprod. 34: 414-423, 2019. [PubMed: 30629171] [Full Text: https://doi.org/10.1093/humrep/dey377]
Quill, T. A., Ren, D., Clapham, D. E., Garbers, D. L. A voltage-gated ion channel expressed specifically in spermatozoa. Proc. Nat. Acad. Sci. 98: 12527-12531, 2001. [PubMed: 11675491] [Full Text: https://doi.org/10.1073/pnas.221454998]
Quill, T. A., Sugden, S. A., Rossi, K. L., Doolittle, L. K., Hammer, R. E., Garbers, D. L. Hyperactivated sperm motility driven by CatSper2 is required for fertilization. Proc. Nat. Acad. Sci. 100: 14869-14874, 2003. [PubMed: 14657366] [Full Text: https://doi.org/10.1073/pnas.2136654100]
Ren, D., Xia, J. Calcium signaling through CatSper channels in mammalian fertilization. Physiology 25: 165-175, 2010. [PubMed: 20551230] [Full Text: https://doi.org/10.1152/physiol.00049.2009]
Smith, J. F., Syritsyna, O., Fellous, M., Serres, C., Mannowetz, N., Kirichok, Y., Lishko, P. V. Disruption of the principal, progesterone-activated sperm Ca(2+) channel in a CatSper2-deficient infertile patient. Proc. Nat. Acad. Sci. 110: 6823-6828, 2013. [PubMed: 23530196] [Full Text: https://doi.org/10.1073/pnas.1216588110]
Zhang, Y., Malekpour, M., Al-Madani, N., Kahrizi, K., Zanganeh, M., Lohr, N. J., Mohseni, M., Mojahedi, F., Daneshi, A., Najmabadi, H., Smith, R. J. H. Sensorineural deafness and male infertility: a contiguous gene deletion syndrome. J. Med. Genet. 44: 233-240, 2007. Note: Erratum: J. Med. Genet. 44: 544 only, 2007. [PubMed: 17098888] [Full Text: https://doi.org/10.1136/jmg.2006.045765]