HGNC Approved Gene Symbol: CCDC8
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:46,410,329-46,413,564 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | 3-M syndrome 3 | 614205 | Autosomal recessive | 3 |
By searching for genes in a potential 3M syndrome locus on chromosome 19q, Hanson et al. (2011) identified CCDC8. The deduced 538-amino acid protein has a calculated molecular mass of 59 kD. It has an N-terminal domain that shares significant similarity with the N-terminal region of PNMA (see 604010), and this is followed by an alanine-rich region that contains a coiled-coil domain, and a second coiled-coil domain at the C terminus. CCDC8 also contains potential sites for amidation, glycosylation, phosphorylation, and myristoylation. RT-PCR analysis detected variable CCDC8 expression in all tissues examined. Western blot analysis detected endogenous CCDC8 at an apparent molecular mass of about 90 kD, suggesting extensive posttranslational modification. Database analysis revealed orthologs of CCDC8 in placental mammals only.
Hanson et al. (2011) observed a strong correlation between the tissue distribution of CCDC8 and that of OBSL1 (610991) and CUL7 (609577), which are also implicated in 3M syndromes (612921 and 273750, respectively). Immunoprecipitation analysis of cotransfected HEK293 cells revealed that OBSL1 interacted with both CCDC8 and CUL7, but CCDC8 did not interact with CUL7. Hanson et al. (2011) proposed that OBSL1 may act as an adaptor protein linking CUL7 and CCDC8.
Hanson et al. (2011) stated that CCDC8 is a single-exon gene.
By database analysis, Hanson et al. (2011) mapped the CCDC8 gene to chromosome 19q13.2-q13.32.
By autozygosity mapping followed by exome sequencing of 3 Asian patients with 3M syndrome-3 (3M3; 614205), Hanson et al. (2011) identified 2 different homozygous 1-bp duplications in the CCDC8 gene (614145.0001 and 614145.0002). Both mutations were predicted to result in truncation, consistent with a loss of function. The phenotype was characterized by poor growth and characteristic dysmorphic features, including fleshy tipped nose, frontal bossing, triangular face, pointed chin, short thorax, and prominent heels. The findings supported the hypothesis that the 3M syndrome results from defects in a pathway controlling human growth.
In 3 Saudi sibs with 3M syndrome, Al-Dosari et al. (2012) identified homozygosity for an insertion/deletion in the CCDC8 gene (614145.0003).
In 2 Pakistani sisters with mild 3M syndrome, Liao et al. (2017) identified homozygosity for a previously reported frameshift mutation in the CCDC8 gene (614145.0001).
In 4 unrelated South Asian patients with 3M syndrome-3 (3M3; 614205), Hanson et al. (2011) identified a homozygous 1-bp duplication (c.612dupG, NM_032040.3) in the CCDC8 gene, causing a frameshift resulting in premature termination (Lys205GlufsTer59), predicted to lead to a loss of function. The mutation was not identified in 611 controls, and haplotype analysis indicated a founder effect for 2 of the patients. The protein consequence of the mutation was referred to as Lys205GlufsTer58 in Figure 1 of the report.
In 2 Pakistani sisters with 3M syndrome, Liao et al. (2017) identified homozygosity for the frameshift mutation in the CCDC8 gene identified by Hanson et al. (2011). The authors noted that the 2 sisters presented a considerably milder phenotype than the previously described patients with this mutation.
In a patient with 3M syndrome-3 (3M3; 614205), Hanson et al. (2011) identified a homozygous 1-bp duplication (c.84dupT, NM_032040.3) in the CCDC8 gene, resulting in a truncation at lys29 (K29X). The mutation was not found in 611 controls. Fibroblast cell lines derived from this patient showed no detectable CCDC8 protein.
In 3 Saudi sibs (family F) with 3M syndrome-3 (3M3; 614205), born of first-cousin parents, Al-Dosari et al. (2012) identified homozygosity for an insertion/deletion in the CCDC8 gene (c.803_807delinsT), causing a frameshift and premature termination (Lys268IlefsTer40).
Al-Dosari, M. S., Al-Shammari, M., Shaheen, R., Faqeih, E., AlGhofely, M. A., Boukai, A., Alkuraya, F. S. 3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature. J. Pediat. 161: 139-145, 2012. [PubMed: 22325252] [Full Text: https://doi.org/10.1016/j.jpeds.2011.12.051]
Hanson, D., Murray, P. G., O'Sullivan, J., Urquhart, J., Daly, S., Bhaskar, S. S., Biesecker, L. G., Skae, M., Smith, C., Cole, T., Kirk, J., Chandler, K., Kingston, H., Donnai, D., Clayton, P. E., Black, G. C. M. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am. J. Hum. Genet. 89: 148-153, 2011. [PubMed: 21737058] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.028]
Liao, L., Gan, H.-W., Hwa, V., Dattani, M., Dauber, A. Two siblings with a mutation in CCDC8 presenting with mild short stature: a case of 3-M syndrome. Horm. Res. Paediat. 88: 364-370, 2017. [PubMed: 28675896] [Full Text: https://doi.org/10.1159/000477907]