HGNC Approved Gene Symbol: ZCCHC8
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:122,471,600-122,500,932 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | ?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 5 | 618674 | Autosomal dominant | 3 |
ZCCHC8 is a nuclear protein that may play a role in RNA metabolism (Gustafson et al., 2005).
By SDS-PAGE and mass spectrometry of HeLa cell proteins, Gustafson et al. (2005) identified ZCCHC8, which cross-reacted with an antibody directed to a GSK3 (see 606784) phosphorylation site in MYC (190080). The CCHC domain of ZCCHC8 is mainly found in nucleic acid-binding proteins. In human cell lines, ZCCHC8 localized to the nucleus, but it was excluded from the nucleolus. It had an apparent molecular mass of 105 kD by SDS-PAGE.
Gustafson et al. (2005) determined that ZCCHC8 was phosphorylated on thr492 (T492) in human cells and cell lines. Total levels of ZCCHC8 increased slightly as cells entered S phase, but T492 phosphorylation increased only as cells entered mitosis. Inhibition of GSK3 via lithium treatment or cotransfection of the AXIN (AXIN1; 603816) GSK3 interaction domain greatly reduced ZCCHC8 T492 phosphorylation. Using ZCCHC8 as bait in tandem affinity purification of HeLa cell lysates, followed by SDS-PAGE and mass spectrometric analysis, Gustafson et al. (2005) found that ZCCHC8 interacted with the RNA-splicing factor RBM7 (612413) and with the DExH box RNA helicase SKIV2L2. Cotransfection of HeLa cells confirmed that ZCCHC8 interacted with epitope-tagged RBM7 and SKIV2L2.
Gable et al. (2019) found that knockdown of ZCCHC8 in HeLa cells using shRNA resulted in decreased levels of TERC (602322). Additional detailed cellular studies showed that ZCCHC8 is required for TERC maturation and telomerase function, particularly mediating TERC 3-prime end targeting to the nuclear RNA exosome.
Hartz (2015) mapped the ZCCHC8 gene to chromosome 12q24.31 based on an alignment of the ZCCHC8 sequence (GenBank BC017704) with the genomic sequence (GRCh38).
In 3 members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-5 (PFBMFT5; 618674), Gable et al. (2019) identified a heterozygous missense mutation in the ZCCHC8 gene (P186L; 616381.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two younger asymptomatic family members who had short telomeres also carried the mutation. The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases. Analysis of patient cells showed a 50% decrease in ZCCHC8 protein levels compared to controls, suggesting that the mutation compromised protein stability. Patient cells also showed dysregulation of RNA processing, with abnormal accumulation of TERC precursors at the expense of mature TERC.
Gable et al. (2019) found that homozygous loss of Zcchc8 in mice resulted in postnatal lethality by 70 days. Zcchc8-null mice showed progressive neurodevelopmental defects, with small brain volume, defective neurogenesis, and hydrocephalus. Some of the features were consistent with a ciliopathy. These abnormalities were associated with defective turnover of low abundance RNA polymerase II (see 180660) transcripts and abnormal accumulation of other low abundance RNAs, including histones and RNAs that encode cilia protein components. The findings were consistent with dysregulation of RNA processing.
In 3 members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-5 (PFBMFT5; 618674), Gable et al. (2019) identified a heterozygous c.557C-T transition in the ZCCHC8 gene, resulting in a pro186-to-leu (P186L) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two younger asymptomatic family members who had short telomeres also carried the mutation. The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases. Analysis of patient cells showed a 50% decrease in ZCCHC8 protein levels compared to controls, suggesting that the mutation compromised protein stability.
Gable, D. L., Gaysinskaya, V., Atik, C. C. Talbot, C. C., Jr., Kang, B., Stanley, S. E., Pugh, E. W., Amat-Codina, N., Schenk, K. M., Arcasoy, M. O., Brayton, C., Florea, L., Armanios, M. ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev. 33: 1381-1396, 2019. [PubMed: 31488579] [Full Text: https://doi.org/10.1101/gad.326785.119]
Gustafson, M. P., Welcker, M., Hwang, H. C., Clurman, B. E. Zcchc8 is a glycogen synthase kinase-3 substrate that interacts with RNA-binding proteins. Biochem. Biophys. Res. Commun. 338: 1359-1367, 2005. [PubMed: 16263084] [Full Text: https://doi.org/10.1016/j.bbrc.2005.10.090]
Hartz, P. A. Personal Communication. Baltimore, Md. 5/21/2015.