Alternative titles; symbols
HGNC Approved Gene Symbol: TRRAP
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38) : 7:98,878,532-99,013,241 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.1 | ?Deafness, autosomal dominant 75 | 618778 | Autosomal dominant | 3 |
| Developmental delay with or without dysmorphic facies and autism | 618454 | Autosomal dominant | 3 |
TRRAP functions as part of a multiprotein coactivator complex with histone acetyltransferase activity that is central to the transcriptional activity of other transcription factors such as MYC (190080) and E2F1 (189971) (summary by McMahon et al., 1998). TRRAP is a large, multidomain protein kinase that works as a cofactor in cells to help mediate histone acetylation. Broadly expressed in many tissues of the body and in the brain, TRRAP is also involved in DNA damage repair and chromatin remodeling (summary by Mavros et al., 2018).
McMahon et al. (1998) described the isolation by affinity purification of a highly conserved 434-kD protein, designated TRRAP, that has homology to the ATM/PI3-kinase family. The predicted 3,828-amino acid protein contains a bipartite nuclear localization signal, a potential leucine zipper, and 2 TPR regions. It also has 8 LXXLL sequences dispersed throughout the protein, a motif associated with several transcriptional coactivators. TRRAP is almost exclusively nuclear in localization.
Vassilev et al. (1998) cloned and characterized the 400-kD PCAF-associated factor referred to as PAF400. They found that PAF400 is almost identical to TRRAP and has significant sequence similarities to the ATM superfamily, including FRAP (601231) and ATR (107410), and to the catalytic subunit of DNAPK (600899). Remarkably, PAF400 and FRAP share sequence similarity in broad regions that cover 80% of the entire PAF400 sequence. PAF is not a protein kinase as judged from the lack of kinase motif and autophosphorylation activity.
Xia et al. (2019) found expression of the Trrap gene in mouse cochlea, suggesting that it may play a role in the development of hearing ability.
McMahon et al. (1998) found that TRRAP interacted with the MYC (190080) N terminus and with the E2F1 (189971) transactivation domain. Expression of transdominant mutants of the TRRAP protein or antisense RNA blocked MYC- and E1A-mediated oncogenic transformation. These data suggest that TRRAP is an essential cofactor for both the MYC and E1A/E2F oncogenic transcription factor pathways.
The NuA4 histone acetyltransferase (HAT) complex is responsible for acetylation of the N-terminal tails of histone H4 (see 602822) and H2A (see 613499) in yeast. Its catalytic subunit, Esa1, is homologous to human TIP60 (HTATIP; 601409). Using affinity purification, Western blot analysis, cell fractionation, immunoprecipitation, and mass spectrometry, Doyon et al. (2004) found that TIP60 and its splice variant, TIP60B/PLIP, were part of a multisubunit NuA4 complex with HAT activity in several human cell lines. They identified human homologs for 11 of the 12 yeast NuA4 subunits, including TRRAP.
Using RNA interference in mouse embryonic stem (ES) cells, Fazzio et al. (2008) found that depletion of any of 7 components of the Tip60-p400 (EP400; 606265) HAT and nucleosome remodeling complex, including Trrap, caused the same phenotype. Unlike normal ES cells, which grow in spherical 3-dimensional colonies, ES cells depleted of any the 7 Tip60-p400 HAT components showed a flattened and elongated morphology, with monolayer growth and reduced cell-cell contacts. These knockdown cells continued to cycle, with reduced cells in S phase and increased cells in G2 phase. The effect of Tip60-p400 HAT component knockdown was unique to ES cells, as negligible changes were observed following knockdown in mouse embryonic fibroblasts.
McMahon et al. (1998) noted that the TRRAP gene corresponds to an EST (GenBank T17018) that has been assigned to 7q21.3-q22.1 by radiation hybrid mapping.
Developmental Delay with or without Dysmorphic Facies and Autism
In an 11-year-old boy with a neurologic/psychiatric phenotype consistent with developmental delay without dysmorphic facies or autism (DEDDFA; 618454), Mavros et al. (2018) identified a de novo heterozygous missense mutation in the TRRAP gene (R1986Q; 603015.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. Mavros et al. (2018) noted that several previous large studies had identified de novo heterozygous TRRAP variants in patients with a wide range of neurodevelopmental or cognitive disorders, including childhood disintegrative disorder and schizophrenia (Gupta et al., 2017 and Xu et al. (2011, 2012)).
In 24 patients, including 2 sibs, with DEDDFA, Cogne et al. (2019) identified 17 different de novo heterozygous missense mutations in the TRRAP gene (see, e.g., 603015.0002-603015.0005). The patients were compiled through international collaboration or through the GeneMatcher program. All of the mutations, which were found by exome sequencing, occurred at conserved residues; none were present in the gnomAD database. Thirteen of the mutations occurred between and including residues 1031-1159; these individuals had a complex, multisystemic syndrome with a wide range of intellectual functioning. Phenotypes of individuals with mutations outside of this residue cluster included autism spectrum disorder, intellectual disability, and epilepsy. Functional studies of the variants were not performed, but analysis of fibroblasts from 2 patients with mutations outside of the 1031-1159 residue cluster (L805F, 603015.0002 and W1866C, 603015.0005) showed differential gene expression patterns compared to controls, with upregulation of genes involved in neurologic function and ion transport. Since all of the mutations identified were missense, Cogne et al. (2019) concluded that they have either a gain-of-function or dominant-negative effect.
Autosomal Dominant Deafness 75
In 4 affected members of a 3-generation Chinese family (SH-05) with adult-onset autosomal dominant deafness-75 (DFNA75; 618778), Xia et al. (2019) identified a heterozygous missense variant in the TRRAP gene (R171C; 603015.0006). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in 500 ethnically matched controls or in individuals of East Asian descent in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. Direct sequencing of the TRRAP gene in 66 patients with sporadic hearing loss identified 3 more heterozygous variants in 3 unrelated patients: D394N, Pro509fs, and E2750D. Functional studies of the latter variants were not performed.
Somatic Mutations
Using exome sequencing, Wei et al. (2011) identified a recurrent somatic ser722-to-phe (S722F) mutation in 6 (4%) of 167 melanoma (see 155600) samples. The S722F mutation occurs in a highly conserved residue and showed increased transformation potential compared to wildtype when transfected into NIH 3T3 cells. These findings suggested that TRRAP may act as an oncogene. Knockdown of the S722F mutant protein with siRNA resulted in increased apoptosis of melanoma cells, indicating that mutant TRRAP was essential for melanoma cell survival.
Cogne et al. (2019) suggested that the phenotype associated with TTRAP mutations could be broadly categorized into 2 main groups. In their study of 24 patients, those with mutations affecting residues 1031-1159 had a more severe disorder, often with multisystem involvement, including renal, cardiac, and genitourinary systems, as well as structural brain abnormalities. Patients with mutations outside of that region tended to have a less severe phenotype with a higher incidence of autism and usually no systemic involvement.
Herceg et al. (2001) showed that a null mutation of Trrap in mice results in preimplantation lethality due to a blocked proliferation of blastocysts. They used an inducible Cre-loxP system to show that loss of Trrap blocks cell proliferation because of aberrant mitotic exit accompanied by cytokinesis failure and endoreduplication. Trrap-deficient cells failed to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and displayed compromised cdk1 activity. Trrap is, therefore, essential for early development and required for the mitotic checkpoint and normal cell cycle progression.
Zebrafish have neuromasts consisting of hair cells and supporting cells that play essential roles in hearing, schooling behavior, predation, and orientation, and hair cells of zebrafish are structurally similar to those within human inner ears. Xia et al. (2019) found that morpholino and targeted knockdown of the trrap gene in zebrafish resulted in dose-dependent changes in the ear compared to controls, including smaller and decreased numbers of neuromasts, fewer hair cells per neuromast, and fewer and thinner stereocilia in the hair cells. Mutant zebrafish also had decreased acoustic startle response and impaired sound-induced fast escape reflex compared to controls, suggesting hearing impairment. Trrap was also found to be expressed in the developing mouse cochlea, suggesting that it may play a role in the development of hearing ability.
In an 11-year-old boy with a neurologic/psychiatric phenotype consistent with developmental delay without dysmorphic facies or autism (DEDDFA; 618454), Mavros et al. (2018) identified a de novo heterozygous c.5957G-A transition (c.5957G-A, NM_003496) in the TRRAP gene, resulting in an arg1986-to-gln (R1986Q) substitution at a conserved residue close to the central cavity, which is a predicted DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. The patient had a nonverbal learning disability, obsessive-compulsive disorder, and major depression with psychotic features that responded to pharmacologic treatment.
In an 8-year-old girl (patient 1) with developmental delay and dysmorphic facies without autism (DEDDFA; 618454), Cogne et al. (2019) identified a de novo heterozygous c.2413C-T transition (c.2413C-T, NM_001244580.1) in the TRRAP gene, resulting in a leu805-to-phe (L805F) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the gnomAD database. Analysis of patient fibroblasts showed differential gene expression patterns compared to controls, with upregulation of genes involved in neurologic function and ion transport.
In 5 unrelated patients (patients 7-11) with developmental delay and dysmorphic facies without autism (DEDDFA; 618454), Cogne et al. (2019) identified a de novo heterozygous c.3127G-A transition (c.3127G-A, NM_001244580.1) in the TRRAP gene, resulting in an ala1043-to-thr (A1043T) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 14-year-old boy (patient 18) with developmental delay with dysmorphic facies and autism (DEDDFA; 618454), Cogne et al. (2019) identified a de novo heterozygous c.5596T-A transversion (c.5596T-A, NM_001244580.1) in the TRRAP gene, resulting in a trp1866-to-arg (W1866R) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In an 8-year-old girl (patient 19) with developmental delay with dysmorphic facies and autism (DEDDFA; 618454), Cogne et al. (2019) identified a de novo heterozygous c.5598G-T transversion (c.5598G-T, NM_001244580.1) in the TRRAP gene, resulting in a trp1866-to-cys (W1866C) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the gnomAD database. Analysis of patient fibroblasts showed differential gene expression patterns compared to controls, with upregulation of genes involved in neurologic function and ion transport.
In 4 affected members of a 3-generation Chinese family (SH-05) with adult-onset autosomal dominant deafness-75 (DFNA75; 618778), Xia et al. (2019) identified a heterozygous c.511C-T transition (c.511C-T, NM_001244580) in the TRRAP gene, resulting in an arg171-to-cys (R171C) substitution at a highly conserved residue. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in 500 ethnically matched controls or in individuals of East Asian descent in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Hamosh (2020) noted that the R171C variant was found in heterozygous state in 8 of 250,870 alleles from other populations in gnomAD, including 3 Latino, 4 non-Finnish Europeans, and 1 South Asian (frequency of 3.2 x 10(-5)) (February 15, 2020).
Cogne, B., Ehresmann, S., Beauregard-Lacroix, E., Rousseau, J., Besnard, T., Garcia, T., Petrovski, S., Avni, S., McWalter, K., Blackburn, P. R., Sanders, S. J., Uguen, K., and 105 others. Missense variants in the histone acetyltransferase complex component gene TRRAP cause autism and syndromic intellectual disability. Am. J. Hum. Genet. 104: 530-541, 2019. [PubMed: 30827496] [Full Text: https://doi.org/10.1016/j.ajhg.2019.01.010]
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Fazzio, T. G., Huff, J. T., Panning, B. An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 134: 162-174, 2008. [PubMed: 18614019] [Full Text: https://doi.org/10.1016/j.cell.2008.05.031]
Gupta, A. R., Westphal, A., Yang, D. Y. J., Sullivan, C. A. W., Eilbott, J., Zaidi, S., Voos, A., Vander Wyk, B. C., Ventola, P., Waqar, Z., Fernandez, T. V, Ercan-Sencicek, A. G, and 11 others. Neurogenetic analysis of childhood disintegrative disorder. Molec. Autism 8: 19, 2017. Note: Electronic Article. [PubMed: 28392909] [Full Text: https://doi.org/10.1186/s13229-017-0133-0]
Hamosh, A. Personal Communication. Baltimore, Md. 2/15/2020.
Herceg, Z., Hulla, W., Gell, D., Cuenin, C., Lleonart, M., Jackson, S., Wang, Z.-Q. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nature Genet. 29: 206-211, 2001. [PubMed: 11544477] [Full Text: https://doi.org/10.1038/ng725]
Mavros, C. F., Brownstein, C. A., Thyagrajan, R., Genetti, C. A., Tembulkar, S., Graber, K., Murphy, Q., Cabral, K., VanNoy, G. E., Bainbridge, M., Shi, J., Agrawal, P. B., Beggs, A. H., D'Angelo, E., Gonzalez-Heydrich, J. De novo variant of TRRAP in a patient with very early onset psychosis in the context of non-verbal learning disability and obsessive-compulsive disorder: a case report. BMC Med. Genet. 19: 197, 2018. Note: Electronic Article. [PubMed: 30424743] [Full Text: https://doi.org/10.1186/s12881-018-0711-9]
McMahon, S. B., Van Buskirk, H. A., Dugan, K. A., Copeland, T. D., Cole, M. D. The novel ATM-related protein TRRAP is an essential cofactor for the c-myc and E2F oncoproteins. Cell 94: 363-374, 1998. [PubMed: 9708738] [Full Text: https://doi.org/10.1016/s0092-8674(00)81479-8]
Vassilev, A., Yamauchi, J., Kotani, T., Prives, C., Avantaggiati, M. L., Qin, J., Nakatani, Y. The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily. Molec. Cell 2: 869-875, 1998. [PubMed: 9885574] [Full Text: https://doi.org/10.1016/s1097-2765(00)80301-9]
Wei, X., Walia, V., Lin, J. C., Teer, J. K., Prickett, T. D., Gartner, J., Davis, S., NISC Comparative Sequencing Program, Stemke-Hale, K., Davies, M. A., Gershenwald, J. E., Robinson, W., Robinson, S., Rosenberg, S. A., Samuels, Y. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nature Genet. 43: 442-446, 2011. [PubMed: 21499247] [Full Text: https://doi.org/10.1038/ng.810]
Xia, W., Hu, J., Ma, J., Huang, J., Wang, X., Jiang, N., Zhang, J., Ma, Z., Ma, D. Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss. Clin. Genet. 96: 300-308, 2019. [PubMed: 31231791] [Full Text: https://doi.org/10.1111/cge.13590]
Xu, B., Ionita-Laza, I., Roos, J. L., Boone, B., Woodrick, S., Sun, Y., Levy, S., Gogos, J. A., Karayiorgou, M. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nature Genet. 44: 1365-1369, 2012. [PubMed: 23042115] [Full Text: https://doi.org/10.1038/ng.2446]
Xu, B., Roos, J. L., Dexheimer, P., Boone, B., Plummer, B., Levy, S., Gogos, J. A., Karayiorgou, M. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nature Genet. 43: 864-868, 2011. [PubMed: 21822266] [Full Text: https://doi.org/10.1038/ng.902]