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HGNC Approved Gene Symbol: CTDP1
SNOMEDCT: 702433001;
Cytogenetic location: 18q23 Genomic coordinates (GRCh38) : 18:79,676,768-79,756,625 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q23 | Congenital cataracts, facial dysmorphism, and neuropathy | 604168 | Autosomal recessive | 3 |
Eukaryotic RNA polymerases are unable to initiate RNA synthesis without additional proteins called general transcription factors, or GTFs. GTFs assemble in a complex on the DNA promoter and recruit the RNA polymerase. Multisubunit GTF complexes, such as TFIIF, are essential for RNA polymerase II-mediated transcription of many, if not all, protein-encoding genes. TFIIF is composed of 2 subunits, RAP30 (GTF2F2; 189969) and RAP74 (GTF2F1; 189968), that mediate interactions with RNA polymerase II. During transcript elongation, the C-terminal domain (CTD) of RNA polymerase II subunit A (POLR2A; 180660) becomes heavily phosphorylated via CCNK (603544). CTDP1 is a phosphatase specific for the CTD of POLR2A (Archambault et al., 1998).
Using a yeast 2-hybrid screen of a peripheral lymphocyte cDNA library to identify cDNAs encoding proteins that interact with RAP74, followed by screening colon carcinoma and fetal brain cDNA libraries, Archambault et al. (1998) isolated cDNAs encoding CTDP1, which they called FCP1 (TFIIF-associating CTD phosphatase-1). One CTDP1 cDNA identified encodes a deduced 842-amino acid protein that the authors termed FCP1A. Another CTDP1 cDNA identified encodes a presumed splice variant, termed FCP1B, that lacks the last 139 amino acids. Northern blot analysis detected a 3.6-kb CTDP1 transcript in all tissues tested, namely heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Immunoblot analysis detected a 150-kD protein in HeLa nuclear extracts.
Using immunoblot analysis, Archambault et al. (1998) showed that CTDP1 copurified precisely with CTD phosphatase activity in HeLa nuclear extracts. Binding analysis showed that the C terminus of CTDP1 bound to the C terminus of RAP74. Archambault et al. (1998) concluded that CTDP1 is an essential subunit of a RAP74-stimulated phosphatase that processively dephosphorylates the C terminus of POLR2A, making it available for initiation of gene expression.
Licciardo et al. (2003) found that FCP1-affinity purified complexes in an FCP1-expressing human lung carcinoma cell line (H1299) contained RNA polymerase II and MEP50 (WDR77; 611734), a component of a complex involved in methylation and assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). Glycerol gradient fractionation and Western blot analysis of H1299 whole cell extracts detected MEP50 in protein complexes of 400 kD and more than 800 kD. In nuclear extracts, MEP50 was associated only with the 400-kD complex, which also appeared to contain FCP1 and was distinct from the larger methyltransferase complex containing PRMT5 (604045). Immunoprecipitation analysis showed that FCP1 interacted specifically with components of the pre-mRNA spliceosomal snRNPs (e.g., SNRP70; 180740). Licciardo et al. (2003) concluded that FCP1 may be involved in linking transcription elongation with splicing.
Varon et al. (2003) found that congenital cataracts with facial dysmorphism and neuropathy (604168), an autosomal recessive disorder that occurs in an endogenous group of Vlax Roma (Gypsies), is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (604927.0001).
In Rudari Vlax Roma (Gypsies) with congenital cataracts with facial dysmorphism and neuropathy (CCFDN; 604168), Varon et al. (2003) found perfect segregation of the disease phenotype with a C-to-T transition in an antisense Alu element in intron 6 of the CTDP1 gene (IVS6+389C-T). Screening of 887 unaffected population controls found a 6.9% carrier rate among the Rudari, in close agreement with predictions based on CCFDN prevalence; an average carrier rate of 0.6% in other Gypsy populations; and a rate of 0.0% among non-Gypsy Europeans. RT-PCR and sequencing analysis identified a rare mechanism of aberrant splicing in which the donor site created by the C-T transition activates an upstream cryptic acceptor site, resulting in the insertion of 95 nucleotides of the Alu sequence in the processed CTDP1 mRNA. This mechanism had been identified previously only in ornithine aminotransferase deficiency (258870.0023). The insertion in the CTDP1 mRNA results in a premature termination signal 17 codons downstream of exon 6, with the mutant transcript expected to undergo nonsense-mediated decay or lead to a nonfunctional protein lacking the nuclear localization signal. Varon et al. (2003) observed an abnormal product in all cell types studied, regardless of their involvement in the clinical phenotype.
Morar et al. (2004) used the IVS6+389C-T mutation and 4 other private mutations among the Roma (Gypsies) to infer some of the missing parameters relevant to the comprehensive characterization of the population history of the Gypsies. Sharing of mutations and high carrier rates supported a strong founder effect.
Archambault, J., Pan, G., Dahmus, G. K., Cartier, M., Marshall, N., Zhang, S., Dahmus, M. E., Greenblatt, J. FCP1, the RAP74-interacting subunit of a human protein phosphatase that dephosphorylates the carboxy-terminal domain of RNA polymerase IIO. J. Biol. Chem. 273: 27593-27601, 1998. [PubMed: 9765293] [Full Text: https://doi.org/10.1074/jbc.273.42.27593]
Licciardo, P., Amente, S., Ruggiero, L., Monti, M., Pucci, P., Lania, L., Majello, B. The FCP1 phosphatase interacts with RNA polymerase II and with MEP50 a component of the methylosome complex involved in the assembly of snRNP. Nucleic Acids Res. 31: 999-1005, 2003. [PubMed: 12560496] [Full Text: https://doi.org/10.1093/nar/gkg197]
Morar, B., Gresham, D., Angelicheva, D., Tournev, I., Gooding, R., Guergueltcheva, V., Schmidt, C., Abicht, A., Lochmuller, H., Tordai, A., Kalmar, L., Nagy, M., and 10 others. Mutation history of the Roma/Gypsies. Am. J. Hum. Genet. 75: 596-609, 2004. [PubMed: 15322984] [Full Text: https://doi.org/10.1086/424759]
Varon, R., Gooding, R., Steglich, C., Marns, L., Tang, H., Angelicheva, D., Yong, K. K., Ambrugger, P., Reinhold, A., Morar, B., Baas, F., Kwa, M., and 14 others. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nature Genet. 35: 185-189, 2003. [PubMed: 14517542] [Full Text: https://doi.org/10.1038/ng1243]