Alternative titles; symbols
HGNC Approved Gene Symbol: TCP1
Cytogenetic location: 6q25.3 Genomic coordinates (GRCh38) : 6:159,778,498-159,789,602 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25.3 | Intellectual developmental disorder with polymicrogyria and seizures | 621021 | Autosomal dominant | 3 |
The TCP1 gene, also known as CCT1, encodes 1 of 8 subunits of the eukaryotic chaperonin TRiC (T-complex protein-1 ring complex), which is a large barrel-shaped oligomeric complex that plays a role in protein folding (summary by Kraft et al., 2024).
A role in the folding of newly translated proteins in the cytosol has been proposed for t-complex polypeptide-1 (TCP1). Tubulin (e.g., 191110) is a major cytosolic protein whose assembly into microtubules is critical to many cellular processes. Yaffe et al. (1992) examined the biogenesis of alpha- and beta-tubulin in rabbit reticulocyte lysate. They found that newly translated tubulin subunits entered a 900-kD complex which contained as its major constituent a 58-kD protein that crossreacted with a monoclonal antiserum against mouse TCP1. This led them to conclude that TCP1 functions as a cytosolic chaperone in the biosynthesis of tubulin.
By use of a cDNA probe for the mouse tcp1 locus, part of the t-complex, Willison et al. (1985) assigned the homologous locus to chromosome 6. The finding was confirmed by means of a cDNA probe for the human TCP1 gene. Suspicion that some human malformations are the result of mutation in the t-complex loci is discussed elsewhere (182940). TCP1 codes for a protein which is abundantly expressed in testes as well as in other tissues. Using the cloned gene and a panel of somatic cell hybrids, as well as in situ hybridization, Willison et al. (1987) assigned the gene to 6q23-qter; thus, it is not closely linked to the HLA complex. For this reason and others, TCP1 is not likely to be a human equivalent of the mouse t-complex. Blanche et al. (1987) found that TCP1 is not linked to HLA and GLO1 and is probably excluded from 6p. This result was consistent with the reported localization to 6q23-qter. By in situ hybridization, Fonatsch et al. (1987) concluded that the TCP1 locus is probably in the 6q25-q27 region. Blanche et al. (1992) demonstrated that the TCP1 and plasminogen (173350) genes show no recombination and are located about 50 cM proximal to TCP10 (187020), which is located in band 6q27.
The ACAT2 gene (100678) shows complementary overlapping with the 3-prime region of the TCP1 gene in both mouse and human. These genes are encoded on opposite strands of DNA, as well as in opposite transcriptional orientation. Masuno et al. (1996) assigned the ACAT2 gene to 6q25.3-q26 by fluorescence in situ hybridization; thus the assignment of the TCP1 gene can be refined to 6q25.3-q26.
In 4 unrelated individuals with intellectual developmental disorder with polymicrogyria and seizures (IDDPMGS; 621021), Kraft et al. (2024) identified de novo heterozygous nonsense or frameshift mutations in the CCT1 gene (186980.0001-186980.0004). No patient cells were available for functional studies. In yeast, expression of the nonsense and frameshift CCT1 variants resulted in variable growth defects under different conditions. However, some of these variants did not adversely affect growth in yeast under certain conditions. The authors concluded that some of the variants result in a loss of function and haploinsufficiency. Four other individual with variable neurodevelopmental disorders carried 2 nonsense and 2 missense variants, only 1 of which (K159R in P7) was demonstrated to occur de novo. This variant occurred in the nucleotide-sensing loop and impaired growth in yeast with evidence of mitochondrial dysfunction. There was evidence of a dominant-negative effect on TRiC function, including microtubule and actin defects. However, P7, a 20-year-old man, did not have seizures, had normal brain imaging, and it was unknown if he had developmental delay or impaired intellectual development. The other missense variant (P38L in P4) did not impair growth in yeast, but caused actin aggregates in C. elegans. Cct1-null heterozygous worms showed crawling defects, suggestive of haploinsufficiency.
In a 10-year-old boy (P2) with intellectual developmental disorder with polymicrogyria and seizures (IDDPMGS; 621021), Kraft et al. (2024) identified a de novo heterozygous 2-bp deletion in the TCP1 gene (c.583_584delGT, NM_030752.3), resulting in a val195-to-ter (V195X) substitution. The variant was not present in the gnomAD database (v4.1.0). Patient cells were not available for study, but yeast studies suggested a loss of function. The patient had a more severe disorder than the other patients reported by Kraft et al. (2024), including severe developmental delay, visual impairment, and seizures. Brain imaging showed polymicrogyria.
In a 31-year-old man (P3) with intellectual developmental disorder with polymicrogyria and seizures (IDDPMGS; 621021), Kraft et al. (2024) identified a de novo heterozygous 4-bp deletion (c.252_255del, NM_030752.3) in the TCP1 gene, predicted to result in a frameshift and premature termination (Glu85LeufsTer16). The variant was not present in the gnomAD database (v4.1.0). Patient cells were not available for study, but yeast studies suggested a loss of function. The patient had mild developmental delay and seizures; polymicrogyria was present on brain imaging.
In a 12-year-old girl (P5) with intellectual developmental disorder with polymicrogyria and seizures (IDDPMGS; 621021), Kraft et al. (2024) identified a de novo heterozygous 1-bp duplication (c.1502dup, NM_030752.3) in the TCP1 gene, predicted to result in a frameshift and premature termination (Gly502ArgfsTer4). The variant was not present in the gnomAD database (v4.1.0). Patient cells were not available for study, but yeast studies suggested a loss of function. The patient had mildly impaired intellectual development, seizures, and polymicrogyria on brain imaging.
In a 13-year-old boy (P6) with intellectual developmental disorder with polymicrogyria and seizures (IDDPMGS; 621021), Kraft et al. (2024) identified a de novo heterozygous 4-bp deletion (c.793_796del, NM_030752.3) in the TCP1 gene, predicted to result in a frameshift and premature termination (Gln265GlufsTer22). The variant was not present in the gnomAD database (v4.1.0). Patient cells were not available for study, but studies in yeast suggested a loss of function. The patient had developmental delay, seizures, and polymicrogyria on brain imaging.
Blanche, H., Massart, C., Dausset, J., Cann, H. TCP1 is not linked to HLA, GLO1, PGK1P2 and other markers in a 45cM map of the short arm of chromosome 6 (6p). (Abstract) Cytogenet. Cell Genet. 46: 581-582, 1987.
Blanche, H., Wright, L. G., Vergnaud, G., de Gouyon, B., Lauthier, V., Silver, L. M., Dausset, J., Cann, H. M., Spielman, R. S. Genetic mapping of three human homologues of murine t-complex genes localizes TCP10 to 6q27, 15 cM distal to TCP1 and PLG. Genomics 12: 826-828, 1992. [PubMed: 1572657] [Full Text: https://doi.org/10.1016/0888-7543(92)90317-l]
Fonatsch, C., Gradl, G., Ragoussis, J., Ziegler, A. Assignment of the TCP1 locus to the long arm of human chromosome 6 by in situ hybridization. Cytogenet. Cell Genet. 45: 109-112, 1987. [PubMed: 3476253] [Full Text: https://doi.org/10.1159/000132439]
Kraft, F., Rodriguez-Aliaga, P., Yuan, W., Franken, L., Zajt, K., Hasan, D., Lee, T. T., Flex, E., Hentschel, A., Innes, A. M., Zheng, B., Julia Suh, D. S., and 75 others. Brain malformations and seizures by impaired chaperonin function of TRiC. Science 386: 516-525, 2024. [PubMed: 39480921] [Full Text: https://doi.org/10.1126/science.adp8721]
Masuno, M., Fukao, T., Song, X.-Q., Yamaguchi, S., Orii, T., Kondo, N., Imaizumi, K., Kuroki, Y. Assignment of the human cytosolic acetoacetyl-coenzyme A thiolase (ACAT2) gene to chromosome 6q25.3-q26. Genomics 36: 217-218, 1996. [PubMed: 8812443] [Full Text: https://doi.org/10.1006/geno.1996.0452]
Willison, K., Dudley, K., Spurr, N., Goodfellow, P. Chromosomal assignment of TCP-1, the human homologue of a mouse t-complex locus. (Abstract) Cytogenet. Cell Genet. 40: 779-780, 1985.
Willison, K., Kelly, A., Dudley, K., Goodfellow, P., Spurr, N., Groves, V., Gorman, P., Sheer, D., Trowsdale, J. The human homologue of the mouse t-complex gene, TCP1, is located on chromosome 6 but is not near the HLA region. EMBO J. 6: 1967-1974, 1987. [PubMed: 3653076] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02459.x]
Yaffe, M. B., Farr, G. W., Miklos, D., Horwich, A. L., Sternlicht, M. L., Sternlicht, H. TCP1 complex is a molecular chaperone in tubulin biogenesis. Nature 358: 245-248, 1992. [PubMed: 1630491] [Full Text: https://doi.org/10.1038/358245a0]