Alternative titles; symbols
HGNC Approved Gene Symbol: TBL1XR1
SNOMEDCT: 1220594007;
Cytogenetic location: 3q26.32 Genomic coordinates (GRCh38): 3:177,019,344-177,201,800 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.32 | Intellectual developmental disorder, autosomal dominant 41 | 616944 | Autosomal dominant | 3 |
| Pierpont syndrome | 602342 | Autosomal dominant | 3 |
The TBL1XR1 gene encodes a protein that localizes to the nucleus and is expressed in most tissues. It interacts with histones H2B (see 609904) and H4 (see 602822), and plays a role in transcription mediated by nuclear receptors (summary by Tabet et al., 2014).
By differential display of transcripts preferentially expressed in CD34 (142230)-positive/CD38 (107270)-negative hematopoietic progenitor cells, followed by screening placenta and erythroleukemia cell cDNA libraries and RACE, Zhang et al. (2000) cloned TBLR1, which they designated C21. The 3-prime UTR of TBLR1 is more than 2 kb long. The deduced 515-amino acid TBLR1 protein contains 4 WD40 repeats and shares significant identity with TBL1 (300196). Northern blot analysis detected transcripts of 4.3 and 7.8 kb in several tissues, including leukemic cells. RNA dot-blot analysis detected widespread expression.
By affinity purification of nuclear corepressor (NCOR; 600849) and histone deacetylase-3 (HDAC3; 605166) complexes, followed by mass spectrometry and SDS-PAGE to identify protein subunits, Zhang et al. (2002) identified TBLR1. They obtained a cDNA encoding TBLR1 by EST database analysis and 5-prime RACE of a HeLa cell cDNA library. Peptide mass fingerprints indicated that TBLR1 was equally represented in both the NCOR and HDAC3 complexes. The TBLR1 protein contains 514 amino acids.
Yoon et al. (2003) purified NCOR complexes, which contained 10 to 12 proteins, from HeLa cell nuclear extracts and characterized the interactions of TBL1 and TBLR1 with NCOR. TBL1 and TBLR1 interacted with NCOR through 2 independent interactions. Their N-terminal regions interacted with the RD1 region of NCOR, and their C-terminal WD40 repeats interacted with the RD4 region of NCOR. In vitro, TBL1 and TBLR1 also bound histones H2B (see 609904) and H4 (see 602822), and transcriptional repression by TBL1 and TBLR1 correlated with their interactions with histones. Using small interfering RNAs, Yoon et al. (2003) demonstrated that HDAC3 was essential for repression by unliganded thyroid hormone receptor. TBL1 and TBLR1 were also essential, but they were functionally redundant.
Perissi et al. (2004) reported that transcriptional activation mediated by liganded nuclear receptors requires the actions of 2 highly related F box/WD40-containing factors, TBL1 and TBLR1. TBL1 and TBLR1 serve as specific adaptors for recruitment of the ubiquitin-conjugating (see 602961)/19S proteasome (see 154365) complex, with TBLR1 selectively serving to mediate a required exchange of the nuclear receptor corepressors, NCOR and SMRT (600848), for coactivators upon ligand binding. Tbl1 gene deletion in murine embryonic stem cells severely impaired PPARG (601487)-induced adipogenic differentiation, indicating that TBL1 function is biologically indispensable for specific nuclear receptor-mediated gene activation events. The role of TBLR1 and TBL1 in cofactor exchange also appeared to operate for JUN (165160) and NFKB (see 164011), suggesting it is likely to be prototypic of similar mechanisms for other signal-dependent transcription factors.
Perissi et al. (2008) found that a large number of regulated transcription factors required both TBL1 and TBLR1 to simultaneously overcome the repressive functions of CTBP1 (602618)/CTBP2 (602619) and NCOR/SMRT corepressor complexes, respectively. TBL1 was specifically required to mediate ubiquitination and degradation of CTBP. Although TBL1 and TBLR1 share a high degree of amino acid identity, the specificity of their activities was regulated by phosphorylation at nonhomologous sites. This phosphorylation was induced by receptor ligands and occurred on TBL1 and TBLR1 prebound to regulated promoters.
Tabet et al. (2014) mapped the TBL1XR1 gene to chromosome 3q26.32 by sequence analysis.
Tabet et al. (2014) reported a 6-year-old girl with nonspecific mild to moderate intellectual disability associated with a de novo heterozygous 1.6-Mb deletion on chromosome 3q26.31-q26.32 involving the TBL1XR1 gene and predicted to result in haploinsufficiency. Brain MRI and EEG were normal, and she did not have autistic features.
Pons et al. (2015) reported an 8-year-old girl and her mother who had the same 708-kb interstitial deletion on chromosome 3q26.32 encompassing only the TBL1XR1 gene; the deletion occurred de novo in the mother. Both individuals had mild to moderate intellectual disability, speech delay, and dysmorphic facial features, including synophrys, mild hypotelorism, depression of the nasal bridge, short nose with anteverted nares, long philtrum, pointed chin, low-set ears, and dental crowding. Clinodactyly and sandal gap were also noted. Autistic features were not present.
Intellectual Developmental Disorder, Autosomal Dominant 41
In a 5-year-old Japanese girl with autosomal dominant intellectual developmental disorder-41 (MRD41; 616944) and autistic features, Saitsu et al. (2014) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (G70D; 608628.0001). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed.
In a girl with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous missense mutation in the TBL1XR1 gene (L282P; 608628.0002). The patient had a nonverbal IQ of 47. Functional studies of the variant were not performed. The patient was from a cohort of 209 parent-child trios exhibiting sporadic autism spectrum disorders who underwent whole-exome sequencing. The same patient was also reported by O'Roak et al. (2012).
In a boy with MRD41 and autistic features, O'Roak et al. (2012) identified a de novo heterozygous truncating mutation in the TBL1XR1 gene (608628.0003). Functional studies of the variant were not performed. The patient was from a cohort of 2,446 autism spectrum disorder probands who underwent sequencing of 44 candidate genes.
Pierpont Syndrome
In 6 unrelated patients with Pierpont syndrome (PRPTS; 602342), including the 2 unrelated patients originally reported by Pierpont et al. (1998), Heinen et al. (2016) identified the same de novo heterozygous missense mutation in the TBL1XR1 gene (Y446C; 608628.0005). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutant protein assembled correctly into its complex, but further functional studies were not performed.
In a male child with Pierpont syndrome, Kahlert et al. (2017) identified heterozygosity for the same missense mutation (Y466C) in the TBL1XR1 gene that was identified by Heinen et al. (2016).
By whole-exome sequencing in 2 unrelated patients with Pierpont syndrome, Lemattre et al. (2018) identified novel de novo heterozygous missense mutations in the TBL1XR1 gene. One mutation (Y446H; 608628.0006) occurred at the same amino acid as the recurrent mutation (Y466C) previously identified in patients with Pierpont syndrome; the other mutation (C325Y; 608628.0007) occurred in the same area of the protein, at the inner surface of the WD40 ring.
By whole-exome sequencing in a boy with Pierpont syndrome, Tesarova et al. (2022) identified the recurrent Y446C mutation in the TBL1XR1 gene. The mutation, which occurred de novo, was confirmed by Sanger sequencing.
In a 5-year-old Japanese girl with autosomal dominant intellectual developmental disorder-41 (MRD41; 616944), Saitsu et al. (2014) identified a de novo heterozygous c.209G-A transition (c.209G-A, NM_024665.4) in the TBL1XR1 gene, resulting in a gly70-to-asp (G70D) substitution at a conserved residue in an F-box-like domain. The mutation, which was found by whole-exome sequencing, was not found in the Exome Sequencing Project database (ESP6500) or in 575 in-house control exomes. Functional studies of the variant were not performed. The patient developed infantile spasms at age 5 months; EEG later showed hypsarrhythmia, and brain MRI revealed no structural brain anomalies; these features were consistent with a clinical diagnosis of West syndrome. She had no eye fixation or pursuit at age 7 months and had mild dysmorphic features. At age 8 months, she developed stereotypic hand movements; at age 5 years, she could walk with support, had a developmental quotient of 13, and showed autistic features.
In a girl with autosomal dominant intellectual developmental disorder-41 (MRD41; 616944) and autistic features, O'Roak et al. (2012) identified a de novo heterozygous mutation in the TBL1XR1 gene, resulting in a leu282-to-pro (L282P) substitution. The patient had a nonverbal IQ of 47. Functional studies of the variant were not performed. The patient was from a cohort of 209 parent-child trios exhibiting sporadic autism spectrum disorders who underwent whole-exome sequencing. The same patient was also reported by O'Roak et al. (2012).
In a boy with autosomal dominant intellectual developmental disorder-41 (MRD41; 616944) and autistic features, O'Roak et al. (2012) identified a de novo heterozygous mutation in the TBL1XR1 gene, resulting in a frameshift and premature termination (Ile397SergsTer19). The patient had a nonverbal IQ of 41. Functional studies of the variant were not performed. The patient was from a cohort of 2,446 autism spectrum disorder probands who underwent sequencing of 44 candidate genes.
In a patient with autosomal dominant intellectual developmental disorder-41 (MRD41; 616944), Armour et al. (2016) identified a de novo heterozygous c.734A-G transition in the TBL1XR1 gene, resulting in a tyr245-to-cys (Y245C) substitution at a highly conserved residue. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The patient was originally reported by Armour et al. (2009) as having spastic paraparesis, brachydactyly, and dysmorphic facial features, but Armour et al. (2016) concluded that these additional features may not have been caused by the TBL1XR1 mutation. Functional studies of the variant were not performed.
In 6 unrelated patients with Pierpont syndrome (PRPTS; 602342), including the patients originally reported by Pierpont et al. (1998), Heinen et al. (2016) identified a de novo heterozygous c.1337A-G transition in the TBL1XR1 gene, resulting in a tyr446-to-cys (Y446C) substitution at a conserved residue in the WD40 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. The mutant protein assembled correctly into its complex, but further functional studies were not performed.
In a male child with Pierpont syndrome, Kahlert et al. (2017) identified heterozygosity for the Y446C mutation in the TBL1XR1 gene. The mutation was confirmed by Sanger sequencing.
By whole-exome sequencing in a boy with Pierpont syndrome, Tesarova et al. (2022) identified heterozygosity for the Y446C mutation in the TBL1XR1 gene. The mutation, which occurred de novo, was confirmed by Sanger sequencing.
In a 24-year-old girl with Pierpont syndrome (PRPTS; 602342), Lemattre et al. (2018) identified a de novo heterozygous c.1336T-C transition (c.1336T-C, NM_024665.4) in the TBL1XR gene, resulting in a tyr446-to-his (Y446H) substitution at the same conserved residue in the WD40 domain that was found in several patients previously reported with Pierpont syndrome (Y446C; 608628.0005). The mutation, which was found by whole-exome sequencing, was not seen in the dbSNP, ESP, ExAC, or gnomAD databases.
In a 14-year-old boy with Pierpont syndrome (PRPTS; 602342), Lemattre et al. (2018) identified a heterozygous c.974G-A transition (c.974G-A, NM_024665.4) in the TBL1XR gene, resulting in a cys325-to-tyr (C325Y) substitution in the inner surface of the WD40 ring. The mutation, which was found by whole-exome sequencing, was not seen in the dbSNP, ESP, ExAC and gnomAD databases.
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Perissi, V., Scafoglio, C., Zhang, J., Ohgi, K. A., Rose, D. W., Glass, C. K., Rosenfeld, M. G. TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints. Molec. Cell 29: 755-766, 2008. [PubMed: 18374649] [Full Text: https://doi.org/10.1016/j.molcel.2008.01.020]
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Pons, L., Cordier, M. P., Labalme, A., Till, M., Louvrier, C., Schluth-Bolard, C., Lesca, G., Edery, P., Sanlaville, D. A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Am. J. Med. Genet. 167A: 164-168, 2015. [PubMed: 25425123] [Full Text: https://doi.org/10.1002/ajmg.a.36759]
Saitsu, H., Tohyama, J., Walsh, T., Kato, M., Kobayashi, Y., Lee, M., Tsurusaki, Y., Miyake, N., Goto, Y., Nishino, I., Ohtake, A., King, M.-C., Matsumoto, N. A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. J. Hum. Genet. 59: 581-583, 2014. [PubMed: 25102098] [Full Text: https://doi.org/10.1038/jhg.2014.71]
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Tesarova, M., Baxova, A., Hansikova, H., Lambert, L., Vondrackova, A., Leiska, A., Zeman, J. Pierpont syndrome due to mutation c.1337A-G in TBL1XR1 gene. Clin. Dysmorph. 31: 145-148, 2022. [PubMed: 35165208] [Full Text: https://doi.org/10.1097/MCD.0000000000000416]
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