Alternative titles; symbols
HGNC Approved Gene Symbol: SYCP2
SNOMEDCT: 236803007;
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:59,863,571-59,933,637 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Spermatogenic failure 1 | 258150 | Autosomal dominant | 3 |
During meiotic prophase, chromosomes are arranged along proteinaceous axes called axial elements. In rat, the major protein components of axial elements are proteins of 30, 33, and 190 kD. The 30- and 33-kD proteins appear to be products of a single gene, Scp3 (SYCP3; 604759). Offenberg et al. (1998) isolated rat testis cDNAs encoding the 190-kD protein, which they designated Scp2. Scp2 is a basic protein, with a pI of 8. It contains 2 clusters of S/T-P motifs, which are common in DNA-binding proteins, and a C-terminal coiled-coil region. Scp2 shows some similarity at the amino acid sequence and secondary structural levels to the S. cerevisiae Red1 protein, which is involved in meiotic recombination and the assembly of axial elements of synaptonemal complexes. Northern blot analysis showed that Scp2 was expressed exclusively in rat testis. Immunocytology localized Scp2 specifically to the synaptonemal complex in the nuclei of rat testis meiotic prophase nuclei.
By screening a human testis library with a partial rat Scp2 cDNA, Schalk et al. (1999) isolated cDNAs encoding human SCP2. The predicted 1,530-amino acid human protein shares 63% amino acid identity with rat Scp2. Like rat Scp2, human SCP2 contains S/T-P motifs, 2 nuclear targeting signals, and a C-terminal coiled-coil region.
By FISH, Schalk et al. (1999) mapped the human SCP2 gene to chromosome 20q13.33.
Offenberg et al. (1998) found that recombinant rat Scp2 bound DNA in Southwestern blot experiments. They speculated that Scp2 is a DNA-binding protein involved in the structural organization of meiotic prophase chromosomes.
Using protein interaction assays, Yang et al. (2006) showed that mouse Sycp2 interacted directly with Sycp3 in vitro and in vivo, and that the interaction required the coiled-coil domain of Sycp2. Western blot analysis of chromatin extracts of mouse testis detected Sycp2, as well as Sycp1 (602162), Sycp3, and histone H3 (see 602810).
Yang et al. (2006) developed a line of mice expressing a mutant Sycp2 in which exon 38 was fused in-frame to exon 44. The mutant protein was expressed, although it was truncated and lacked the C-terminal coiled-coil domain. Homozygous mutant mice were obtained at a normal mendelian ratio and appeared normal, but males were sterile, and females were subfertile with sharply reduced litter size. Heterozygous Sycp2 mutant males and females showed normal fertility. Homozygous Sycp2 mutant spermatocytes exhibited complete meiotic arrest, failed to differentiate into pachytene spermatocytes, and underwent apoptosis in type II seminiferous tubules due to failure in the formation of axial elements and chromosomal synapsis. Homozygous Sycp2 mutant fetal oocytes showed homologous chromosome alignment, but full chromosome synapsis was interrupted by prominent axial gaps in the synaptonemal complex. The mutant Sycp2 protein localized to axial chromosomal cores in both spermatocytes and fetal oocytes, but Sycp3 did not and formed nuclear aggregates. Furthermore, mutant Sycp2 only loosely bound chromatin. Yang et al. (2006) concluded that SYCP2 is a primary determinant of axial elements and lateral elements and is required for incorporation of SYCP3 into synaptonemal complexes.
In a 28-year-old man (DGAP230) with a 2-year history of infertility and severe oligozoospermia (see 258150), Schilit et al. (2020) identified the apparently balanced reciprocal translocation 46,XY,t(20;22)(q13.3;q11.2). Breakpoint analysis yielded 20 candidate genes that were disrupted or potentially dysregulated, and expression analysis by qPCR revealed that SYCP2 expression in the patient's lymphoblastoid cell line (LCL) was increased more than 20-fold compared to control LCLs. Misexpression of SYCP2 appeared to derive exclusively from the der(20) allele, and further analysis of the der(20) chromosome supported an enhancer adoption model, in which an active enhancer residing in the segment of chromosome 22 translocated to the der(20) may enter a newly formed chromatin contact encompassing the cis-residing SYCP2 allele, resulting in illegitimate overexpression. Overexpression of the yeast functional homolog of SYCP2, RED1, resulted in aberrant assembly of the synaptonemal complex in budding yeast meiotic nuclei. The authors suggested that an abnormal abundance of SYCP2 axial element protein disrupted homologous chromosome synapsis in patient DGAP230, resulting in severe oligozoospermia due to asynapsis-triggered cell death in spermatocytes.
Schilit et al. (2020) examined exome sequencing data from a male infertility cohort and identified 3 men with oligo- or azoospermia (spermatogenic failure-1, SPGF1; 258150) who had heterozygous truncating variants in the SYCP2 gene (604105.0001-604105.0003) that were not found in the gnomAD or TOPMed databases.
In a 39-year-old man (M1401) with infertility and azoospermia, who had meiotic arrest at the pachytene spermatocyte stage (SPGF1; 258150), Schilit et al. (2020) identified heterozygosity for a 5-bp deletion (c.3067_3071del, NM_014258.3) in exon 33 of the SYCP2 gene, causing a frameshift predicted to result in a premature termination codon (Lys1023LeufsTer2). The mutation was not found in the gnomAD or TOPMed databases.
In a 27-year-old infertile man (M1581) with cryptozoospermia (SPGF1; 258150), Schilit et al. (2020) identified heterozygosity for a 5-bp deletion (c.2793_2797del, NM_014258.3) in exon 31 of the SYCP2 gene, causing a frameshift predicted to result in a premature termination codon (Lys932SerfsTer3). The mutation, which was inherited from his unaffected mother, was not found in the gnomAD or TOPMed databases.
In a 29-year-old infertile man (M1686) with cryptozoospermia (SPGF1; 258150), Schilit et al. (2020) identified heterozygosity for a 5-bp deletion (c.2022_2025del, NM_014258.3) in exon 24 of theSYCP2 gene, causing a frameshift predicted to result in a premature termination codon (Lys674AsnfsTer8). The mutation was not found in the gnomAD or TOPMed databases.
Offenberg, H. H., Schalk, J. A. C., Meuwissen, R. L. J., van Aalderen, M., Kester, H. A., Dietrich, A. J. J., Heyting, C. SCP2: a major protein component of the axial elements of synaptonemal complexes of the rat. Nucleic Acids Res. 26: 2572-2579, 1998. [PubMed: 9592139] [Full Text: https://doi.org/10.1093/nar/26.11.2572]
Schalk, J. A. C., Offenberg, H. H., Peters, E., Groot, N. P. B., Hoovers, J. M. N., Heyting, C. Isolation and characterization of the human SCP2 cDNA and chromosomal localization of the gene. Mammalian Genome 10: 642-644, 1999. [PubMed: 10341103] [Full Text: https://doi.org/10.1007/s003359901062]
Schilit, S. L. P., Menon, S., Friedrich, C., Kammin, T., Wilch, E., Hanscom, C., Jiang, S., Kliesch, S., Talkowski, M. E., Tuttelmann, F., MacQueen, A. J., Morton, C. C. SYCP2 translocation-mediated dysregulation and frameshift variants cause human male infertility. Am. J. Hum. Genet. 106: 41-57, 2020. [PubMed: 31866047] [Full Text: https://doi.org/10.1016/j.ajhg.2019.11.013]
Yang, F., De La Fuente, R., Leu, N. A., Baumann, C., McLaughlin, K. J., Wang, P. J. Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J. Cell Biol. 173: 497-507, 2006. [PubMed: 16717126] [Full Text: https://doi.org/10.1083/jcb.200603063]