Alternative titles; symbols
HGNC Approved Gene Symbol: CATSPER1
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:66,016,752-66,026,479 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Spermatogenic failure 7 | 612997 | Autosomal recessive | 3 |
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, CATSPER2 (607249), 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).
While searching for calcium channels, Ren et al. (2001) identified an EST cDNA expressed only in testis. They cloned the corresponding full-length cDNA from human and mouse testis by PCR and library screening. The CATSPER gene encodes a protein of 686 amino acids that is expressed exclusively in testis. The amino acid sequence of CATSPER most closely resembles a single 6-transmembrane-spanning repeat of the voltage-dependent calcium channel 4-repeat structure. Human CATSPER exhibits a high degree of homology (55% identity) with its mouse counterpart, especially in the transmembrane domains and histidine-rich region. The transmembrane domains share 81% identity and the pore regions 89% identity. Using immunofluorescence, Ren et al. (2001) detected the expression of CATSPER within the principal piece of the sperm tail.
Kirichok et al. (2006) used a simple approach to patch-clamp spermatozoa and to characterize whole-spermatozoan currents and identified a constitutively active flagellar calcium channel that is strongly potentiated by intracellular alkalinization. This current is not present in spermatozoa lacking the sperm-specific putative ion channel protein Catsper1. This plasma membrane protein of the 6 transmembrane-spanning ion channel superfamily is specifically localized to the principal piece of the sperm tail and is required for sperm cell hyperactivation and male fertility (Ren et al., 2001; Carlson et al., 2003). Kirichok et al. (2006) concluded that their results identified Catsper1 as a component of the key flagellar calcium channel, and suggested that intracellular alkalinization potentiates Catsper current to increase intraflagellar calcium and induce sperm hyperactivation.
Strunker et al. (2011) demonstrated that progesterone activates the sperm-specific, pH-sensitive CatSper calcium ion channel. They found that both progesterone and alkaline pH stimulate a rapid calcium ion influx with almost no latency, incompatible with a signaling pathway involving metabotrophic receptors and second messengers. The calcium ion signals evoked by alkaline pH and progesterone were inhibited by 2 Ca(V) channel blockers. Patch-clamp recordings from sperm revealed an alkaline-activated current carried by mono- and divalent ions that exhibited all the hallmarks of sperm-specific CatSper calcium ion channels. Progesterone substantially enhanced the CatSper current. The alkaline- and progesterone-activated CatSper current was inhibited by both Ca(V) channel blockers. Strunker et al. (2011) concluded that their results resolved a long-standing controversy over the nongenomic progesterone signaling. In human sperm, either the CatSper channel itself or an associated protein serves as the nongenomic progesterone receptor.
Lishko et al. (2011) elucidated the mechanism of the nongenomic action of progesterone on human spermatozoa by identifying the calcium ion channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, Lishko et al. (2011) found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent calcium ion channel of the sperm flagellum. Lishko et al. (2011) demonstrated that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because their experimental conditions did not support second messenger signaling, CatSper or a directly associated protein may serve as the elusive nongenomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm-specific and structurally different from the genomic progesterone receptor (607311), it represents a promising target for the development of a new class of nonhormonal contraceptives.
By mass spectrometric analysis of proteins that bound a biotin-tagged progesterone analog, Miller et al. (2016) determined that ABHD2 (612196) functions as the progesterone receptor in flagellum of human spermatozoa. Progesterone stimulated the lipid hydrolase activity of ABHD2, which catalyzed conversion of 2-arachidonoylglycerol (2AG) to arachidonic acid and glycerol. ABHD2-dependent depletion of 2AG in sperm membrane relieved inhibition of CATSPER1 by 2AG, resulting in calcium influx and sperm activation. In contrast, in mouse sperm flagellum, which has low resting AG levels, Catsper1 was not inhibited. Abhd2 was detected only in the acrosomal region of mouse sperm, and both progesterone and arachidonic acid stimulated the acrosome reaction in mouse sperm.
Avenarius et al. (2009) noted that the CATSPER1 gene comprises 12 coding exons.
Avenarius et al. (2009) identified the CATSPER1 gene on chromosome 11q13.1 by genomic sequence analysis.
In 3 infertile males with spermatogenic failure-7 (612997) from 2 consanguineous Iranian families, Avenarius et al. (2009) identified homozygosity for 1 of 2 separate insertion mutations in the CATSPER1 gene. CATSPER1 is one of 4 members of the sperm-specific CATSPER voltage-gated calcium channel family shown to be essential for normal male fertility in mice. The results suggested that CATSPER1 is also essential for normal male fertility in humans.
To study its function in vivo, Ren et al. (2001) disrupted mouse Catsper in embryonic stem cells by homologous recombination. Catsper homozygous-deficient mice were born at expected mendelian ratios and were indistinguishable from wildtype littermates in survival rates, appearance, and gross behavior. Homozygous-deficient females mated with heterozygous-deficient or wildtype males were fertile. Homozygous male mutants mated with wildtype females displayed mounting behavior indistinguishable from that of wildtype males but were completely infertile. Body and testis weights of the mutant mice were not different from those of wildtype counterparts; sperm counts were not significantly different, and sperm appeared morphologically similar. However, Catsper -/- sperm were sluggish and displayed less directed movements. Further investigation indicated that Catsper is required to penetrate the egg. Catsper -/- sperm incubated with zona pellucida-free eggs were able to fertilize the eggs, indicating that Catsper is not required for egg activation. Ren et al. (2001) demonstrated that Catsper is required for cAMP-induced calcium influx.
In 2 brothers from a consanguineous Iranian family with nonsyndromic infertility (SPGF7; 612997), Avenarius et al. (2009) identified homozygosity for insertion of a thymine at nucleotide 539 in exon 1 of the CATSPER1 gene. This insertion was predicted to introduce 8 novel amino acids followed by a premature termination codon into the CATSPER1 protein (Lys180LysfsTer8). If the aberrant transcript is not subject to nonsense-mediated decay, a severely truncated 188-amino acid protein would be translated. This mutation was not identified in 576 Iranian control individuals.
In a male from a consanguineous Iranian family with nonsyndromic infertility (612997), Avenarius et al. (2009) identified homozygosity for a 5-bp insertion after nucleotide 948 in exon 1 of the CATSPER1 gene. The frameshift caused by this insertion was predicted to substitute a methionine at asp317 and introduce 18 novel residues before a premature stop codon (Asp317MetfsTer18). In the absence of nonsense-mediated decay, the predicted product would be a truncated 335-residue protein. The mutation was also found in homozygosity in 1 female family member. It was not identified in 576 Iranian control individuals.
Avenarius, M. R., Hildebrand, M. S., Zhang, Y., Meyer, N. C., Smith, L. L. H., Kahrizi, K., Najmabadi, H., Smith, R. J. H. Human male infertility caused by mutations in the CATSPER1 channel protein. Am. J. Hum. Genet. 84: 505-510, 2009. [PubMed: 19344877] [Full Text: https://doi.org/10.1016/j.ajhg.2009.03.004]
Carlson, A. E., Westenbroek, R. E., Quill, T., Ren, D., Clapham, D. E., Hille, B., Garbers, D. L., Babcock, D. F. CatSper1 required for evoked Ca(2+) entry and control of flagellar function in sperm. Proc. Nat. Acad. Sci. 100: 14864-14868, 2003. [PubMed: 14657352] [Full Text: https://doi.org/10.1073/pnas.2536658100]
Kirichok, Y., Navarro, B., Clapham, D. E. Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca(2+) channel. Nature 439: 737-740, 2006. [PubMed: 16467839] [Full Text: https://doi.org/10.1038/nature04417]
Lishko, P. V., Botchkina, I. L., Kirichok, Y. Progesterone activates the principal Ca2+ channel of human sperm. Nature 471: 387-391, 2011. [PubMed: 21412339] [Full Text: https://doi.org/10.1038/nature09767]
Miller, M. R., Mannowetz, N., Iavarone, A. T., Safavi, R., Gracheva, E. O., Smith, J. F., Hill, R. Z., Bautista, D. M., Kirichok, Y., Lishko, P. V. Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science 352: 555-559, 2016. [PubMed: 26989199] [Full Text: https://doi.org/10.1126/science.aad6887]
Ren, D., Navarro, B., Perez, G., Jackson, A. C., Hsu, S., Shi, Q., Tilly, J. L., Clapham, D. E. A sperm ion channel required for sperm motility and male fertility. Nature 413: 603-609, 2001. [PubMed: 11595941] [Full Text: https://doi.org/10.1038/35098027]
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]
Strunker, T., Goodwin, N., Brenker, C., Kashikar, N. D., Weyand, I., Seifert, R., Kaupp, U. B. The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 471: 382-386, 2011. [PubMed: 21412338] [Full Text: https://doi.org/10.1038/nature09769]