Alternative titles; symbols
HGNC Approved Gene Symbol: TCF20
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38) : 22:42,160,013-42,343,537 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.2 | Developmental delay with variable intellectual impairment and behavioral abnormalities | 618430 | Autosomal dominant | 3 |
TCF20 contains over 1,900 amino acids and harbors several functional domains. It is predicted to function as a transcriptional activator or repressor depending on its interaction with other factors (summary by Gburcik et al., 2005).
Sanz et al. (1995) screened a mouse fibroblast expression library to identify factors that bind to a 19-nucleotide promoter element called the SPRE (stromelysin-1 PDGF-responsive element), which controls stromelysin-1 (185250) expression in response to mitogen stimulation. They isolated a cDNA encoding a predicted 937-amino acid protein designated SPBP for 'SPRE-binding protein.' SPBP contains several features characteristic of transcription factors, including a putative leucine zipper region, a nuclear localization signal, and a basic domain similar to the DNA-binding domain found in the Fos (164810)-Jun (165160) family of transcription factors. However, whereas in Fos and Jun the ZIP and DNA-binding domains lie very close together, in SPBP they are widely separated.
Rajadhyaksha et al. (1998) identified cDNAs encoding AR1, a human SPBP homolog.
Sanz et al. (1995) found that expression of SPBP in mammalian cells activated transcription of a reporter gene construct containing either the full-length stromelysin promoter or a single copy of the SPRE inserted upstream of a heterologous promoter.
Estrogen receptor (ER)-alpha (ESR1; 133430) has 2 activation function (AF) domains, and AF1 near its N terminus is activated by serine phosphorylation. Using a phage display to screen for the proteins in a human breast expression cDNA library that were recruited to phosphoactivated AF1, Gburcik et al. (2005) identified SPBP. SPBP interacted predominantly with AF1 phosphorylated on ser118, a MAP kinase (see 176948) phosphorylation site. In vitro, recombinant SPBP also interacted with an AF1 phosphoserine mimic, ser118 to glu. Mutation analysis revealed that SPBP interacted with phosphorylated AF1 via a basic region near its C-terminal end. When expressed in 293T cells, SPBP interacted with ER-alpha in an estradiol-dependent fashion. Endogenous SPBP and ER-alpha coprecipitated from MCF7 breast cancer cell lysates only in the presence of hormone, and overexpression of SPBP reduced both basal- and estradiol-induced MCF7 cell proliferation. Inhibitor and expression studies revealed that histone deacetylases (see 601241) and nuclear receptor corepressor (see NCOR1, 600849) were involved in SPBP-dependent ER-alpha repression, and that the C-terminal basic region of SPBP was insufficient to reverse ER-alpha activation.
By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Rajadhyaksha et al. (1998) localized the AR1 gene to 22q13.3.
In a 25-year-old woman (family 6) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Babbs et al. (2014) identified a de novo heterozygous frameshift mutation in the TCF20 gene (603107.0001). Analysis of patient cells showed that the mutation escaped nonsense-mediated mRNA decay and would likely produce a truncated protein. Five patients from 4 additional families with autism spectrum disorder were found to carry heterozygous missense variants affecting conserved residues in the TCF20 gene (K512E and P1557L); the P1557L variant was present in unaffected parents. In addition, functional studies of these missense variants were not performed.
In 2 unrelated boys with DDVIBA, Schafgen et al. (2016) identified de novo heterozygous mutations in the TCF20 gene (603107.0002 and 603107.0003). One was a nonsense mutation and the other was a frameshift; functional studies of the variants and studies of patient cells were not performed. The mutations were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. The patients were ascertained from a cohort of 313 individuals with intellectual disability who underwent trio-based whole-exome sequencing.
In 28 patients from 27 unrelated families, including a set of monozygotic twins (patients 27 and 28), with DDVIBA, Vetrini et al. (2019) identified 25 heterozygous mutations in the TCF20 gene (see, e.g., 603107.0004-603107.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing; none were found in the ExAC or gnomAD databases. Most of the mutations were predicted to result in a loss of function: there were 18 frameshifts, 5 nonsense, 1 splice site, and 1 missense (K1710R). Most of the mutations occurred de novo, although there were 4 families in which the pathogenic mutation was inherited from an affected parent; the parents tended to have a milder phenotype. Four additional patients carried heterozygous deletions ranging from 128 kb to 2.64 Mb that disrupted the TCF20 gene. A few patients carried additional variants in other genes, which may have contributed to the phenotype. Functional studies of the variants and studies of most patient cells were not performed. However, RNA studies of 3 of the variants that were predicted to cause premature termination showed that they escaped nonsense-mediated mRNA decay. No genotype/phenotype correlations were observed.
In 27 patients from 24 families with DDVIBA, Torti et al. (2019) identified heterozygous mutations in the TCF20 gene (see, e.g., 603107.0007-603107.0009). The patients were ascertained from several clinical and research centers, and the mutations were found by exome sequencing with Sanger confirmation. Almost all mutations occurred de novo; germline mosaicism was demonstrated or predicted in 2 familial cases. There were 23 frameshift or nonsense mutations, all predicted to result in a loss of function, and 1 missense mutation. Functional studies of the variants and studies of patient cells were not performed, but none of the variants were present in large population cohorts. Several patients carried possible pathogenic variants in other genes, which may have contributed to the phenotype.
In a 25-year-old woman (family 6) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Babbs et al. (2014) identified a de novo heterozygous 1-bp deletion (c.3518delA, NM_005650.1) in exon 2 of the TCF20 gene, resulting in a frameshift and premature termination (Lys1173ArgfsTer5). The mutation was found by exome sequencing. Analysis of patient-derived lymphoblastoid cells showed that the mutant transcript escaped nonsense-mediated mRNA decay, predicting the expression of a truncated protein lacking the C-terminal PEST domain.
In a 14-year-old boy (patient 1) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Schafgen et al. (2016) identified a de novo heterozygous c.955C-T transition (c.955C-T, NM_005650.3) in exon 2 of the TCF20 gene, resulting in a gln319-to-ter (Q319X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 5,165 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 14-year-old boy (patient 2) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Schafgen et al. (2016) identified a de novo heterozygous 1-bp deletion (c.3837delA, NM_005650.3) in exon 2 of the TCF20 gene, resulting in a frameshift and premature termination (Asp1280IlefsTer71). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 5,165 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 3-year-old boy (patient 1) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Vetrini et al. (2019) identified a heterozygous 4-bp duplication (c.310_313dupCCAC, NM_005650.3) in exon 2 of the TCF20 gene, predicted to result in a frameshift and premature termination (Gln106ProfsTer30). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the mother, who was less severely affected. The mutation was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and likely haploinsufficiency.
In a 14-year-old girl (patient 2) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Vetrini et al. (2019) identified a de novo heterozygous 1-bp duplication (c.594dupT, NM_005650.3) in exon 2 of the TCF20 gene, predicted to result in a frameshift and premature termination (Gly199TrpfsTer56). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and likely haploinsufficiency.
In a 3-year-old boy (patient 4) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Vetrini et al. (2019) identified a de novo heterozygous 1-bp deletion (c.1520delC, NM_005650.3) in exon 2 of the TCF20 gene, predicted to result in a frameshift and premature termination (Pro507LeufsTer5). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and likely haploinsufficiency.
In a 9-year-old girl (patient 3) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Torti et al. (2019) identified a de novo heterozygous c.697C-T transition (c.697C-T, NM_005650.1) in the TCF20 gene, resulting in a gln233-to-ter (Q233X) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In a 13-year-old girl (patient 7) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Torti et al. (2019) identified a heterozygous c.1960C-T transition (c.1960C-T, NM_005650.1) in the TCF20 gene, resulting in a gln654-to-ter (Q654X) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Inheritance from the patient's mother was excluded but the father was not tested. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
In 2 sibs (patients 10a and 10b) with developmental delay with variable intellectual impairment and behavioral abnormalities (DDVIBA; 618430), Torti et al. (2019) identified a heterozygous c.2224C-T transition (c.2224C-T, NM_005650.1) in the TCF20 gene, resulting in an arg742-to-ter (R742X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not detected in the unaffected parents, suggesting germline mosaicism. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function.
Babbs, C., Lloyd, D., Pagnamenta, A. T., Twigg, S. R. F., Green, J., McGowan, S. J., Mirza, G., Naples, R., Sharma, V. P., Volpi, E. V., Buckle, V. J., Wall, S. A., Knight, S. J. L., International Molecular Genetic Study of Autism Consortium (IMGSAC), Parr, J. R., Wilkie, A. O. M. De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder. J. Med. Genet. 51: 737-747, 2014. [PubMed: 25228304] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102582]
Gburcik, V., Bot, N., Maggiolini, M., Picard, D. SPBP is a phosphoserine-specific repressor of estrogen receptor-alpha. Molec. Cell. Biol. 25: 3421-3430, 2005. [PubMed: 15831449] [Full Text: https://doi.org/10.1128/MCB.25.9.3421-3430.2005]
Rajadhyaksha, A., Riviere, M., Van Vooren, P., Szpirer, J., Szpirer, C., Babin, J., Bina, M. Assignment of AR1, transcription factor 20 (TCF20), to human chromosome 22q13.3 with somatic cell hybrids and in situ hybridization. Cytogenet. Cell Genet. 81: 176-177, 1998. [PubMed: 9730594] [Full Text: https://doi.org/10.1159/000015021]
Sanz, L., Moscat, J., Diaz-Meco, M. T. Molecular characterization of a novel transcription factor that controls stromelysin expression. Molec. Cell. Biol. 15: 3164-3170, 1995. [PubMed: 7760812] [Full Text: https://doi.org/10.1128/MCB.15.6.3164]
Schafgen, J., Cremer, K., Becker, J., Wieland, T., Zink, A. M., Kim, S., Windheuser, I. C., Kreiss, M., Aretz, S., Strom, T. M., Wieczorek, D., Engels, H. De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth. Europ. J. Hum. Genet. 24: 1739-1745, 2016. [PubMed: 27436265] [Full Text: https://doi.org/10.1038/ejhg.2016.90]
Torti, E., Keren, B., Palmer, E. E., Zhu, Z., Afenjar, A., Anderson, I. J., Andrews, M. V., Atkinson, C., Au, M., Berry, S. A., Bowling, K. M., Boyle, J., and 41 others. Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature. Genet. Med. 21: 2036-2042, 2019. [PubMed: 30739909] [Full Text: https://doi.org/10.1038/s41436-019-0454-9]
Vetrini, F., McKee, S., Rosenfeld, J. A., Suri, M., Lewis, A. M., Nugent, K. M., Roeder, E., Littlejohn, R. O., Holder, S., Zhu, W., Alaimo, J. T., Graham, B., and 46 others. De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome. Genome Med. 11: 12, 2019. Note: Electronic Article. Erratum: Genome Med 11: 16, 2019. [PubMed: 30819258] [Full Text: https://doi.org/10.1186/s13073-019-0623-0]