Alternative titles; symbols
HGNC Approved Gene Symbol: CCDC34
Cytogenetic location: 11p14.1 Genomic coordinates (GRCh38): 11:27,338,512-27,363,215 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p14.1 | Spermatogenic failure 76 | 620084 | Autosomal recessive | 3 |
The CCDC34 gene encodes an evolutionarily conserved protein containing a coiled-coil domain, which is related to ciliary and flagellar functions (summary by Cong et al., 2022).
Using autologous antibody, Scanlan et al. (1999) cloned CCDC34, which they designated NY-REN-41, from a renal cell carcinoma cDNA library. RT-PCR detected expression in all normal tissues tested, including lung, testis, small intestine, breast, liver, and placenta.
Cong et al. (2022) stated that the CCDC34 gene encodes a 373-amino acid protein. By immunofluorescence staining of human spermatozoa, Cong et al. (2022) observed CCDC34 signal primarily in the midpiece, as well as weak distribution in the principal piece. In mice, Ccdc34 was mainly expressed in the midpiece of sperm flagella, and testicular sections showed localization primarily in the elongating spermatids.
By genomic sequence analysis, Taylor et al. (2006) mapped the CCDC34 gene to chromosome 11p14.1.
By whole-exome sequencing in 2 cohorts of infertile men with multiple morphologic abnormalities of the flagella, including 100 men from China and 167 men from North Africa, Iran, and France, Cong et al. (2022) identified 2 men with spermatogenic failure due to oligoasthenoteratozoospermia (SPGF76; 620084) and homozygous frameshift mutations in the CCDC34 gene: a Chinese man with a 1-bp duplication (612324.0001), and an Iranian man with an 19-bp deletion (612324.0002).
Using CRISPR/Cas9 technology, Cong et al. (2022) generated mice with a frameshift mutation in the Ccdc34 gene. Homozygous males were infertile, whereas homozygous females had normal fertility when mated with wildtype mice. Semen analysis in the infertile males showed significantly lower sperm concentrations, motility, and progressive motility compared to wildtype controls. TUNEL assay showed a high level of apoptosis in the testes of Ccdc34-mutated male mice, suggesting that decreased sperm concentrations might be caused by aberrant apoptosis of testicular cells. Cross-sections of testicular tissue from the mutant mice showed no elongating spermatids in the seminiferous tubules, and few spermatozoa were observed in sections from the cauda epididymis. Hematoxylin-eosin staining of spermatozoa showed a typical multiple morphologic abnormalities of the flagella (MMAF) phenotype, with significantly higher rates of absent, short, bent, coiled, and irregular-caliber flagella in the mutant mice than in controls. Ultrastructural analysis showed an abnormal 9+2 structure and displacement of the outer dense fibers in the midpiece, abnormalities that the authors noted were similar to those seen in patients with CCDC34-associated infertility. Immunofluorescence assays showed that Ccdc34 was almost absent from the sperm cells and testes of mutant mice. Analysis of expression and localization of Ift52 (617094), a component of the anterograde ciliary transport complex, revealed its absence from the flagellar midpiece and from elongating spermatids in the mutant mice. The authors suggested that Ccdc34 deficiency likely influences sperm flagellar formation through an abnormal anterograde intraflagellar transport system.
In an infertile Chinese man (family Y003) with oligoasthenoteratozoospermia due to multiple morphologic abnormalities of the flagella (MMAF) (SPGF76; 620084), Cong et al. (2022) identified homozygosity for a 1-bp duplication (c.731dup, NM_030771.2) in the CCDC34 gene, causing a frameshift predicted to result in a premature termination codon (Asn244LysfsTer3) with destruction of the coiled-coil domain. His unaffected parents were heterozygous for the duplication, which was not found in the 1000 Genomes Project database but was present in the gnomAD database at very low minor allele frequency (MAF overall, 8.5 x 10(-5); MAF in East Asians, 3.2 x 10 (-4)). RT-qPCR analysis of mRNA from patient sperm cells showed markedly reduced expression of CCDC34, which was confirmed by Western blot analysis. Immunofluorescence staining showed that CCDC34 signal was almost absent in patient sperm flagella compared to control, which showed signal primarily in the midpiece as well as in the principal piece. In addition, IFT20 (614394) and IFT52 (617094), components of the anterograde ciliary transport complex, were markedly reduced in the patient compared to control.
In an infertile Iranian man (family P231) with oligoasthenoteratozoospermia due to multiple morphologic abnormalities of the flagella (MMAF) (SPGF76; 620084), Cong et al. (2022) identified homozygosity for an 19-bp deletion (c.799_817del, NM_030771.2) in the CCDC34 gene, causing a frameshift predicted to result in a premature termination codon (Glu267LysfsTer72) with destruction of the coiled-coil domain. DNA was unavailable from members of family P231; the deletion was not found in the 1000 Genomes Project or gnomAD databases.
Cong, J., Wang, X., Amiri-Yekta, A., Wang, L., Kherraf, Z.-E., Liu, C., Cazin, C., Tang, S., Hosseini, S. H., Tian, S., Daneshipour, A., Wang, J., and 9 others. Homozygous mutations in CCDC34 cause male infertility with oligoasthenoteratozoospermia in humans and mice. J. Med. Genet. 59: 710-718, 2022. [PubMed: 34348960] [Full Text: https://doi.org/10.1136/jmedgenet-2021-107919]
Scanlan, M. J., Gordan, J. D., Williamson, B., Stockert, E., Bander, N. H., Jongeneel, V., Gure, A. O., Jager, D., Jager, E., Knuth, A., Chen, Y.-T., Old, L. J. Antigens recognized by autologous antibody in patients with renal-cell carcinoma. Int. J. Cancer 83: 456-464, 1999. [PubMed: 10508479] [Full Text: https://doi.org/10.1002/(sici)1097-0215(19991112)83:4<456::aid-ijc4>3.0.co;2-5]
Taylor, T. D., Noguchi, H., Totoki, Y., Toyoda, A., Kuroki, Y., Dewar, K., Lloyd, C., Itoh, T., Takeda, T., Kim, D.-W., She, X., Barlow, K. F., and 22 others. Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature 440: 497-500, 2006. [PubMed: 16554811] [Full Text: https://doi.org/10.1038/nature04632]