Alternative titles; symbols
HGNC Approved Gene Symbol: TAF2
Cytogenetic location: 8q24.12 Genomic coordinates (GRCh38) : 8:119,730,774-119,832,841 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.12 | Intellectual developmental disorder, autosomal recessive 40 | 615599 | Autosomal recessive | 3 |
Eukaryotic RNA polymerases are unable to initiate RNA synthesis in the absence of additional proteins called general transcription factors, or GTFs. GTFs assemble in a complex on the DNA promoter and recruit the RNA polymerase. The multisubunit complex TFIID and other GTFs are essential for RNA polymerase II-mediated transcription of many, if not all, protein-encoding genes. TFIID consists of TATA box-binding protein (TBP; 600075), which is a universal GTF for all 3 RNA polymerases, and several TBP-associated factors, or TAFs (e.g., TAF2A; 313650).
Kaufmann et al. (1996) identified CIF, an essential multisubunit cofactor for TFIID-dependent transcription from promoters containing initiator (Inr) elements. Functional and immunologic experiments determined that the 150-kD component of CIF is the mammalian homolog of the Drosophila TAFII150 protein. By screening a HeLa cell cDNA library using degenerate oligonucleotides based on a mouse EST with homology to Drosophila TAFII150, Kaufmann et al. (1998) isolated a human cDNA encoding TAF2B, which they called CIF150. The TAF2B gene encodes a deduced 1,199-amino acid protein. Sequence analysis showed that the TAF2B protein shares 53% amino acid identity with the Drosophila homolog and contains a stretch of 7 histidine residues near the C terminus. Functional analysis showed that TAF2B mediates Inr function requiring TFIID and TBP. Immunoblot analysis, however, was unable to show an association between TAF2B and TFIID. Kaufmann et al. (1998) did observe an association between TAF2B and TAF2C1 (601796).
Through cognate cDNA cloning, Martinez et al. (1998) obtained a cDNA encoding TAF2B. Northern blot analysis detected comparable expression of a single 5.7-kb TAF2B transcript in all tissues tested. In contrast to the findings of Kaufmann et al. (1998), immunoblot analysis showed that TAF2B is stably associated with TFIID, including TAF2C1, TAF2D (601787), and TBP. Martinez et al. (1998) observed that additional cofactors are required for Inr function and transcription.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M177, they identified a homozygous missense mutation in the TAF2 gene (W649R; 604912.0001) in 2 sibs with neurodevelopmental disorder and foot deformity (NEDFCF; 615599),
In 4 children from a consanguineous Arab Bedouin family with neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity, Hellman-Aharony et al. (2013) identified 2 homozygous missense variants in the TAF2 gene (T186R, 604912.0002 and P416H, 604912.0003). The T186R substitution occurred at a more conserved residue than the P416H variant, but was unclear which of the 2 variants, or whether both together, were responsible for the phenotype. The patients had delayed psychomotor development, postnatal microcephaly, pyramidal signs, and thin corpus callosum. Functional studies of the variants were not performed.
In 3 sibs, born to consanguineous parents from North Africa, with NEDFCF, Lesieur-Sebellin et al. (2021) identified a homozygous missense mutation in the TAF gene (P844L; 604912.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. The mutation in this family had previously been reported by Thevenon et al. (2016) but the clinical description was limited. Lesieur-Sebellin et al. (2021) also identified a homozygous missense mutation in the TAF2 gene (Y794N; 604912.0005) by whole-exome sequencing in an unrelated patient from North Africa with NEDFCF who was born to consanguineous parents.
In 2 Arab sibs, born of consanguineous parents, with neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity (NEDFCF; 615599), Najmabadi et al. (2011) identified a trp649-to-arg (W649R) substitution at a conserved residue in the TAF2 gene. Functional studies were not performed.
This variant is classified as a variant of unknown significance because the patients reported by Halevy et al. (2012) and Hellman-Aharony et al. (2013) with neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity (NEDFCF; 615599) were homozygous for 2 mutations in the TAF2 gene (see 604912.0003) and it was unclear which of the 2 variants or whether both together were responsible for the phenotype.
In 4 children from a consanguineous Arab Bedouin family with autosomal recessive mental retardation, Hellman-Aharony et al. (2013) identified 2 homozygous mutations in the TAF2 gene: a c.557C-G transversion in exon 5, resulting in a thr186-to-arg (T186R) substitution at a relatively conserved position in the peptidase domain, and a c.1517C-A transversion in exon 10, resulting in a pro416-to-his (P416H; 604912.0003) substitution at a lesser conserved region outside of the peptidase domain. The mutations were found by candidate gene sequencing of a region on chromosome 8q previously found by linkage analysis in this family (Halevy et al., 2012). The unaffected parents were heterozygous for both mutations. Neither mutation was found in the 1000 Genomes Project database; the T186R mutation was not found in 404 control Arab chromosomes and the P416H mutation was not found in 536 control Arab chromosomes. Functional studies of the variants were not performed. The patients had delayed psychomotor development, postnatal microcephaly, pyramidal signs, and thin corpus callosum.
This variant is classified as a variant of unknown significance because its contribution to neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity (NEDFCF; 615599) has not been confirmed.
See 604912.0002 and Hellman-Aharony et al. (2013).
In 3 sibs, born to consanguineous parents from North Africa, with neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity (NEDFCF; 615599), Lesieur-Sebellin et al. (2021) identified a homozygous c.2531C-T transition (c.2531C-T, NM_003184.4) in exon 19 of the TAF2 gene, resulting in a pro844-to-leu (P844L) substitution at a conserved residue in an Armadillo-type fold protein domain. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was present in the gnomAD database at an allele frequency of 0.00003583. The mutation in this family had previously been reported by Thevenon et al. (2016), but the clinical description was limited and the nucleotide change was described as c.2531G-A (NM_003184.3).
In a female patient, born to consanguineous parents from North Africa, with neurodevelopmental disorder with feeding difficulties, thin corpus callosum, and foot deformity (NEDFCF; 615599), Lesieur-Sebellin et al. (2021) identified a homozygous c.2380T-A transversion (c.2380T-A, NM_003184.4) in exon 19 of the TAF2 gene, resulting in a tyr794-to-asn (Y794N) substitution at a conserved residue in an Armadillo-type fold protein domain. The mutation, which was found by whole-exome sequencing, was identified in the carrier state in the parents. The mutation was not present in the gnomAD database.
Halevy, A., Basel-Vanagaite, L., Shuper, A., Helman, S., Har-Zahav, A., Birk, E., Maya, I., Kornreich, L., Inbar, D., Nurnberg, G., Nurnberg, P., Steinberg, T., Straussberg, R. Microcephaly-thin corpus callosum syndrome maps to 8q23.2-q24.12. Pediat. Neurol. 46: 363-368, 2012. [PubMed: 22633631] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2012.03.014]
Hellman-Aharony, S., Smirin-Yosef, P., Halevy, A., Pasmanik-Chor, M., Yeheskel, A., Har-Zahav, A., Maya, I., Straussberg, R., Dahary, D., Haviv, A., Shohat, M., Basel-Vanagaite, L. Microcephaly thin corpus callosum intellectual disability syndrome caused by mutated TAF2. Pediat. Neurol. 49: 411-416, 2013. [PubMed: 24084144] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2013.07.017]
Kaufmann, J., Ahrens, K., Koop, R., Smale, S. T., Muller, R. CIF150, a human cofactor for transcription factor IID-dependent initiator function. Molec. Cell. Biol. 18: 233-239, 1998. [PubMed: 9418870] [Full Text: https://doi.org/10.1128/MCB.18.1.233]
Kaufmann, J., Verrijzer, C. P., Shao, J., Smale, S. T. CIF, an essential cofactor for TFIID-dependent initiator function. Genes Dev. 10: 873-886, 1996. [PubMed: 8846923] [Full Text: https://doi.org/10.1101/gad.10.7.873]
Lesieur-Sebellin, M., Capri, Y., Grisval, M., Courtin, T., Burtz, A., Thevenon, J., Buratti, J., Lejeune, E., Faivre, L., Keren, B. Phenotype associated with TAF2 biallelic mutations: a clinical description of four individuals and review of the literature. Europ. J. Med. Genet. 64: 104323, 2021. [PubMed: 34474177] [Full Text: https://doi.org/10.1016/j.ejmg.2021.104323]
Martinez, E., Ge, H., Tao, Y., Yuan, C.-X., Palhan, V., Roeder, R. G. Novel cofactors and TFIIA mediate functional core promoter selectivity by the human TAFII150-containing TFIID complex. Molec. Cell. Biol. 18: 6571-6583, 1998. [PubMed: 9774672] [Full Text: https://doi.org/10.1128/MCB.18.11.6571]
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Thevenon, J., Duffourd, Y., Masurel-Paulet, A., Lefebvre, M., Feillet, F., El Chehadeh-Djebbar, S., St-Onge, J., Steinmetz, A., Huet, F., Chouchane, M., Darmency-Stamboul, V., Callier, P., Thauvin-Robinet, C., Faivre, L., Riviere, J. B. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin. Genet. 89: 700-707, 2016. [PubMed: 26757139] [Full Text: https://doi.org/10.1111/cge.12732]