* 604616

T-BOX, BRAIN, 1; TBR1


HGNC Approved Gene Symbol: TBR1

Cytogenetic location: 2q24.2     Genomic coordinates (GRCh38): 2:161,416,297-161,425,870 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q24.2 Intellectual developmental disorder with autism and speech delay 606053 AD 3

TEXT

Description

The TBR1 gene encodes a neuron-specific transcription factor of the T-box family that plays a central role during cortical neurogenesis (summary by Vegas et al., 2018 and McDermott et al., 2018).


Cloning and Expression

Using subtractive hybridization of day 14.5 embryonic telencephalon and adult telencephalon, Bulfone et al. (1995) identified a mouse cDNA for Tbr1 (T-brain-1). Using mouse Tbr1 as a probe to screen a week 17 human fetal cDNA library, the authors identified a TBR1 cDNA encoding a 682-amino acid protein. The sequence of the TBR1 protein is 99% identical to the mouse sequence; both show high homology, particularly in the T-box DNA-binding domain, with the protein product of the T (Brachyury) gene (see 601397). Northern blot and in situ hybridization analyses revealed that expression of mouse Tbr1 is largely restricted to the cerebral cortex. It is expressed in postmitotic cells in the forebrain with onset during embryogenesis and continues to be expressed in the adult brain. Expression is 10-fold more abundant in embryonic than in adult tissue.

Ueno et al. (2000) found reciprocal expression of Tbr1 and Tbr2 (EOMES; 604615) during development of the mouse brain.


Gene Function

To identify binding partners for the guanylate kinase domain of CASK (300172), Hsueh et al. (2000) carried out a yeast 2-hybrid screen of brain cDNA libraries, from which TBR1 was isolated. By deletion analysis, the C-terminal region of TBR1 (residues 342 to 681) was found to be necessary and sufficient for association with the guanylate kinase domain of CASK. When coexpressed in COS-7 cells, TBR1 and CASK were readily coprecipitated by antibodies directed against either individual protein. Hsueh et al. (2000) demonstrated that CASK enters the nucleus and binds to a specific DNA sequence (the T element) in a complex with TBR1. CASK acts as a coactivator of TBR1 to induce transcription of T element-containing genes, including reelin, a gene that is essential for cerebrocortical development.

Deriziotis et al. (2014) demonstrated that TBR1 forms homodimers and interacts with FOXP2 (605317) most likely through the T-box domain. Mutations in the FOXP2 gene, which cause a speech-language disorder (SPCH1; 602081), were found to interrupt the interaction with TBR1.

Den Hoed et al. (2018) demonstrated that TBR1 interacts with the long isoform of BCL11A (606557).

In a review of published literature, Vegas et al. (2018) noted that TBR1 has an established role in patterning of the central nervous system, including regulation of laminar and regional neuronal identities during cortical development. It is part of the PAX6 (607108)-TBR2 (604615)-NEUROD (601724)-TBR1 transcription factor cascade that is critical for controlling glutamatergic neuronal cell fate in the cortex, cerebellum, and hippocampus. By interacting with CASK and FOX2P, TBR1 regulates several genes, including GRIN2B (138252) and RELN (600514), which are necessary for proper neuronal migration during corticogenesis. All of these genes have been reported to be mutated in various forms of intellectual disability, autism, and malformations of cortical development, suggesting a common pathway.


Mapping

By linkage analysis with a mouse mapping panel, Bulfone et al. (1995) mapped the Tbr1 gene to chromosome 2. By homology of synteny, the human TBR1 gene is predicted to map to chromosome 2q23-q37.

Gross (2019) mapped the TBR1 gene to chromosome 2q24.2 based on an alignment of the TBR1 sequence (GenBank BC104844) with the genomic sequence (GRCh38).


Molecular Genetics

In 4 unrelated patients with impaired intellectual development with autism and speech delay (IDDAS; 606053), Deriziotis et al. (2014) identified 4 different de novo heterozygous mutations in the TBR1 gene (604616.0001-604616.0004). There were 2 frameshift mutations, resulting in premature termination, and 2 missense mutations at highly conserved residues in the T-box domain. In vitro functional expression studies using cellular transfection models (HEK293 cells and SHSY5Y neuroblastoma cells) showed that the frameshift mutations resulted in nonfunctional proteins that lost nuclear localization, lost the interaction with CASK and FOXP2, and had deficient transcriptional repression activity compared to wildtype. Furthermore, these mutations may have resulted in nonsense-mediated mRNA decay, but patient tissue was not available for study. The findings related to these mutations were consistent with haploinsufficiency. Similar in vitro studies of the missense variants showed that they retained some transcriptional repression activity, suggesting that DNA-binding activity was not completely abolished, although they were unable to interact with FOXP2. These variants were able to interact with CASK and homodimerize with wildtype TBR1 to form abnormal aggregates in the nucleus. The findings related to these mutations suggested a dominant-negative effect. The patients carrying loss-of-function mutations had more severe cognitive impairment than those with missense mutations. Several additional missense variants were found in patients that had been inherited from unaffected parents. Functional studies of the inherited variants showed that they had little or no impact on TBR1 function, suggesting that inherited TBR1 mutations do not have a role in autism, although minor contributions in conjunction with additional unidentified variants in other genes could not be excluded. The study also suggested that disruption of TBR1-FOXP2 interactions, caused by mutations in either gene, result in speech and language deficits, thus providing a mechanistic bridge between neurodevelopmental disorders.

In 2 unrelated patients with IDDAS, den Hoed et al. (2018) identified de novo heterozygous mutations in the TBR1 gene that affected conserved residues in the T-box domain (604616.0005 and 604616.0006). In vitro functional expression studies in HEK293 cells showed that these mutant proteins retained the ability to repress luciferase activity, were able form homodimers with TBR1, and colocalized with CASK, but formed abnormal aggregates in the nucleus, suggesting a dominant-negative effect. The mutations abolished the TBR1-FOXP2 (605317) interaction.

In 2 unrelated patients with IDDAS, McDermott et al. (2018) identified de novo heterozygous mutations in the TBR1 gene (G316X and L311P). Functional studies of the variants were not performed.

In 2 unrelated boys with IDDAS, Vegas et al. (2018) identified the same de novo heterozygous frameshift mutation in the TBR1 gene (604616.0007). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the mutation may lead to disruption of the downstream RELN pathway. Both patients had malformations of cortical development, including pachygyria, on brain imaging, thus expanding the phenotype associated with TBR1 mutations.


Animal Model

Hevner et al. (2001) developed mice with targeted disruption of the Tbr1 gene. Mutant mice died shortly after birth in the absence of hand feeding. The cortex of neonatal mutants was approximately normal size, but early-born neurons, which guide early neuronal migrations and axonal projections, showed molecular and functional defects. Early-born cells formed a preplate but did not express markers of Cajal-Retzius, subplate, or layer 6 neurons. Cajal-Retzius cells expressed decreased levels of reelin (600514), resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. Markers of later-born cortical layers were relatively normal, and other properties of cortical neurons, such as neurotransmitter expression, cell death, and neuronal morphology, were mostly unaffected.

Huang et al. (2014) showed that haploinsufficiency of Tbr1 in mice resulted in features of autism, including impaired social interaction, impaired vocalization, and impaired cognition and memory. Examination of the brain from Tbr1 +/- mice showed defective axonal projection of neurons in the amygdala. Tbr-null mice had severely impaired neuronal migration in the cerebral cortex.

Fazel Darbandi et al. (2018) generated mice with conditional Tbr1 deletion during late gestation in cortical layer-6 neurons. Gene expression analysis of wildtype and mutant mice demonstrated that late gestational/neonatal Tbr1 expression maintained layer-6 identity in postnatal cortex. Tbr1 directly controlled transcription of genes that define the molecular properties of layer-6 pyramidal neurons and functioned as an activator or repressor. Examination of corticothalamic projections in mutant mice showed that, after about embryonic day 17.5, Tbr1 was required for maturation of corticothalamic connectivity, preferentially in anterior and anteromedial thalamus. Mutant mice exhibited synaptic deficits with reduced number of excitatory synapses, altered cortical interneuron lamination, and reduced inhibitory synaptic density. Restoring expression of Wnt7b (601967), which was dysregulated in mutant mouse neurons, rescued the synaptic deficits of mutant mice. Hyperpolarization-activated cation currents were increased in both heterozygous and homozygous Tbr1 mutant mice. Behavioral analysis showed that neonatal Tbr1 deletion in layer-6 neurons led to increased anxiety-like behavior in heterozygotes and increased aggressive behavior in homozygous mutants.


ALLELIC VARIANTS ( 7 Selected Examples):

.0001 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, 1-BP DEL, C
  
RCV000735639

In a 7-year-old boy (11480.p1) with impaired intellectual development and autism (IDDAS; 606053), Deriziotis et al. (2014) identified a de novo heterozygous 1-bp deletion in the TBR1 gene (chr2.162,273,322delC, GRCh37), resulting in frameshift and premature termination (Ala136ProfsTer80), and predicted to result in a protein lacking the functional T-box domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) reported that this patient had a verbal IQ of 24, nonverbal IQ of 41, and was nonverbal at the time of the report; language delay and language regression were also noted. Cellular transfection studies of the mutation showed that a truncated protein was expressed at higher levels compared to wildtype, but had aberrant subcellular localization with diffuse distribution in the cytoplasm and only some nuclear localization. In addition, the mutant protein lost its transcriptional repressive ability in a luciferase assay, interrupted the TBR1 interaction with CASK (300172), abolished the interaction with FOXP2 (605317), and was unable to form homodimers with wildtype TBR1. Deriziotis et al. (2014) noted that the mutation may have resulted in nonsense-mediated mRNA decay, but patient cells were not available. The findings were consistent with haploinsufficiency.


.0002 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, 1-BP INS, C
  
RCV000735640

In an 8-year-old girl (13796.p1) with intellectual disability and autism (IDDAS; 606053), Deriziotis et al. (2014) identified a de novo heterozygous 1-bp insertion in the TBR1 gene (chr2.162,275,481insC, GRCh37) resulting in a ser351-to-ter (S351X) substitution predicted to result in a protein lacking the functional T-box domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) reported that this patient had a verbal IQ of 69, nonverbal IQ of 63, and had phrase speech at the time of the report; language delay without language regression was also noted. Cellular transfection of the mutant showed that a truncated protein was expressed at lower levels compared to wildtype, but had aberrant subcellular localization with diffuse distribution in the cytoplasm and formation of large aggregates. In addition, the mutant protein lost its transcriptional repressive ability in a luciferase assay, interrupted the TBR1 interaction with CASK (300172), abolished the interaction with FOXP2 (605317), and was unable to form homodimers with wildtype TBR1. Deriziotis et al. (2014) noted that the mutation may have resulted in nonsense-mediated mRNA decay, but patient cells were not available. The findings were consistent with haploinsufficiency.


.0003 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, LYS228GLU
  
RCV000735641

In a 7-year-old boy (13814.p1) with intellectual disability and autism (IDDAS; 606053), Deriziotis et al. (2014) identified a de novo heterozygous A-to-G transition in the TBR1 gene (chr2.162,273,603A-G, GRCh37), resulting in a lys228-to-glu (K228E) substitution at a highly conserved residue in the T-box domain, which is involved in DNA binding and protein-protein interactions. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) reported that this patient had a verbal IQ of 75, nonverbal IQ of 78, and was verbally fluent at the time of the report; language delay without language regression was also noted. The patient had also been diagnosed with developmental coordination disorder. Cellular transfection of the mutant protein showed that it was imported into the nucleus, but formed abnormal aggregates. The mutant protein partially lost its transcriptional repressive ability in a luciferase assay, suggesting retention of partial DNA-binding capacity. The mutant protein retained the ability to homodimerize with wildtype TBR1 and to interact with CASK (300173), suggesting a dominant-negative effect, but was unable to interact with FOXP2 (605317).


.0004 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, ASN374HIS
  
RCV000735642

In a patient (09C86232A) with mild cognitive impairment and autism spectrum disorder (IDDAS; 606053), Deriziotis et al. (2014) reported a de novo heterozygous A-to-C transversion (chr2.162,275,553A-C, GRCh37) in the TBR1 gene, resulting in an asn374-to-his (N374H) substitution at a highly conserved residue in the T-box domain, which is involved in DNA binding and protein-protein interactions. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) stated that this patient had a nonverbal IQ of 74. In vitro cellular expression studies showed that the mutant protein was imported into the nucleus, but formed abnormal aggregates. The mutant protein only partially lost its transcriptional repressive ability in a luciferase assay, suggesting retention of partial DNA-binding capacity. The mutant protein retained the ability to homodimerize with wildtype TBR1 and to interact with CASK (300173), suggesting a dominant-negative effect, but was unable to interact with FOXP2 (605317).


.0005 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, TRP271CYS
  
RCV000735643

In a patient (09C86693) with autism and intellectual disability (IDDAS; 606053), den Hoed et al. (2018) reported a de novo heterozygous c.813G-T transversion (c.813G-T, NM_006593) in the TBR1 gene, resulting in a typ271-to-cys (W271C) substitution. The patient was from a large cohort of individuals with autism who underwent exome sequencing. Den Hoed et al. (2018) noted that the W271C mutation occurs in the T-box domain. Using in vitro functional expression studies in HEK293 cells, den Hoed et al. (2018) showed that the mutant W271C protein retained the ability to repress luciferase activity, but was able to form homodimers with TBR1 and colocalized with CASK in the nucleus to form abnormal aggregates, suggesting a dominant-negative effect. The mutation also abolished the TBR1-FOXP2 (605317) interaction. A different variant affecting the same residue (W271R) was identified in another patient, but functional studies did not show significant adverse effects on TBR1 function. The mutant protein also showed greater stability compared to wildtype TBR1.


.0006 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, LYS389GLU
  
RCV000735644

In a patient (220-9833-201) with autism and intellectual disability (IDDAS; 606053), den Hoed et al. (2018) reported a de novo heterozygous c.1165A-G transition (c.1165A-G, NM_006593) in the TBR1 gene, resulting in a lys389-to-glu (K389E) substitution in the T-box domain. In vitro functional expression studies in HEK293 cells showed that the mutant protein retained the ability to repress luciferase activity, was able form homodimers with TBR1, and colocalized with CASK, but formed abnormal aggregates in the nucleus, suggesting a dominant-negative effect. The mutation abolished the TBR1-FOXP2 (605317) interaction. The mutant protein also showed greater stability compared to wildtype TBR1.


.0007 INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, 7-BP DUP, NT1588
  
RCV000209932...

In 2 unrelated boys with intellectual disability and autism (IDDAS; 606053), Vegas et al. (2018) identified the same de novo heterozygous 7-bp duplication (c.1588_1594dup, NM_006593.3) in exon 6 of the TBR1 gene, resulting in a frameshift and premature termination (Thr532ArgfsTer144) in the CASK (300172)-interacting domain. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the mutation may lead to disruption of the downstream RELN pathway (see 600514). Both patients had malformations of cortical development, including pachygyria, on brain imaging, thus expanding the phenotype associated with TBR1 mutations.


REFERENCES

  1. Bulfone, A., Smiga, S. M., Shimamura, K., Peterson, A., Puelles, L., Rubenstein, J. L. R. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15: 63-78, 1995. [PubMed: 7619531, related citations] [Full Text]

  2. den Hoed, J., Sollis, E., Venselaar, H., Estruch, S. B., Deriziotis, P., Fisher, S. E. Functional characterization of TBR1 variants in neurodevelopmental disorder. Sci. Rep. 8: 14279, 2018. [PubMed: 30250039, images, related citations] [Full Text]

  3. Deriziotis, P., O'Roak, B. J., Graham, S. A., Estruch, S. B., Dimitropoulou, D., Bernier, R. A., Gerdts, J., Shendure, J., Eichler, E. E., Fisher, S. E. De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature Commun. 5: 4954, 2014. Note: Electronic Article. [PubMed: 25232744, images, related citations] [Full Text]

  4. Fazel Darbandi, S., Robinson Schwartz, S. E., Qi, Q., Catta-Preta, R., Pai, E. L.-L., Mandell, J. D., Everitt, A., Rubin, A., Krasnoff, R. A., Katzman, S., Tastad, D., Nord, A. S., Willsey, A. J., Chen, B., State, M. W., Sohal, V. S., Rubenstein, J. L. R. Neonatal Tbr1 dosage controls cortical layer 6 connectivity. Neuron 100: 831-845, 2018. [PubMed: 30318412, images, related citations] [Full Text]

  5. Gross, M. B. Personal Communication. Baltimore, Md. 4/23/2019.

  6. Hevner, R. F., Shi, L., Justice, N., Hsueh, Y.-P., Sheng, M., Smiga, S., Bulfone, A., Goffinet, A. M., Campagnoni, A. T., Rubenstein, J. L. R. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29: 353-366, 2001. [PubMed: 11239428, related citations] [Full Text]

  7. Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M. Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002. [PubMed: 10749215, related citations] [Full Text]

  8. Huang, T.-N., Chuang, H.-C., Chou, W.-H., Chen, C.-Y., Wang, H.-F., Chou, S.-J., Hsueh, Y.-P. Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nature Neurosci. 17: 240-247, 2014. [PubMed: 24441682, related citations] [Full Text]

  9. McDermott, J. H., DDD Study, Clayton-Smith, J., Briggs, T. A. The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum. Europ. J. Med. Genet. 61: 253-256, 2018. [PubMed: 29288087, related citations] [Full Text]

  10. Ueno, M., Kimura, N., Nakashima, K., Saito-Ohara, F., Inazawa, J., Taga, T. Genomic organization, sequence and chromosomal localization of the mouse Tbr2 gene and a comparative study with Tbr1. Gene 254: 29-35, 2000. [PubMed: 10974533, related citations] [Full Text]

  11. Vegas, N., Cavallin, M., Kleefstra, T., de Boer, L., Philbert, M., Maillard, C., Boddaert, N., Munnich, A., Hubert, L., Bery, A., Besmond, C., Bahi-Buisson, N. Mutations in TBR1 gene leads to cortical malformations and intellectual disability. Europ. J. Med. Genet. 61: 759-764, 2018. [PubMed: 30268909, related citations] [Full Text]


Matthew B. Gross - updated : 04/23/2019
Bao Lige - updated : 02/13/2019
Cassandra L. Kniffin - updated : 12/07/2018
Patricia A. Hartz - updated : 7/8/2003
Patricia A. Hartz - updated : 4/29/2002
Ada Hamosh - updated : 3/28/2000
Creation Date:
Paul J. Converse : 2/25/2000
alopez : 02/28/2022
mgross : 04/23/2019
mgross : 02/13/2019
mgross : 02/13/2019
carol : 02/11/2019
alopez : 01/02/2019
alopez : 12/19/2018
alopez : 12/19/2018
alopez : 12/19/2018
alopez : 12/19/2018
ckniffin : 12/07/2018
terry : 07/27/2012
mgross : 7/8/2003
carol : 4/30/2002
terry : 4/29/2002
carol : 3/28/2000
carol : 2/28/2000

* 604616

T-BOX, BRAIN, 1; TBR1


HGNC Approved Gene Symbol: TBR1

Cytogenetic location: 2q24.2     Genomic coordinates (GRCh38): 2:161,416,297-161,425,870 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q24.2 Intellectual developmental disorder with autism and speech delay 606053 Autosomal dominant 3

TEXT

Description

The TBR1 gene encodes a neuron-specific transcription factor of the T-box family that plays a central role during cortical neurogenesis (summary by Vegas et al., 2018 and McDermott et al., 2018).


Cloning and Expression

Using subtractive hybridization of day 14.5 embryonic telencephalon and adult telencephalon, Bulfone et al. (1995) identified a mouse cDNA for Tbr1 (T-brain-1). Using mouse Tbr1 as a probe to screen a week 17 human fetal cDNA library, the authors identified a TBR1 cDNA encoding a 682-amino acid protein. The sequence of the TBR1 protein is 99% identical to the mouse sequence; both show high homology, particularly in the T-box DNA-binding domain, with the protein product of the T (Brachyury) gene (see 601397). Northern blot and in situ hybridization analyses revealed that expression of mouse Tbr1 is largely restricted to the cerebral cortex. It is expressed in postmitotic cells in the forebrain with onset during embryogenesis and continues to be expressed in the adult brain. Expression is 10-fold more abundant in embryonic than in adult tissue.

Ueno et al. (2000) found reciprocal expression of Tbr1 and Tbr2 (EOMES; 604615) during development of the mouse brain.


Gene Function

To identify binding partners for the guanylate kinase domain of CASK (300172), Hsueh et al. (2000) carried out a yeast 2-hybrid screen of brain cDNA libraries, from which TBR1 was isolated. By deletion analysis, the C-terminal region of TBR1 (residues 342 to 681) was found to be necessary and sufficient for association with the guanylate kinase domain of CASK. When coexpressed in COS-7 cells, TBR1 and CASK were readily coprecipitated by antibodies directed against either individual protein. Hsueh et al. (2000) demonstrated that CASK enters the nucleus and binds to a specific DNA sequence (the T element) in a complex with TBR1. CASK acts as a coactivator of TBR1 to induce transcription of T element-containing genes, including reelin, a gene that is essential for cerebrocortical development.

Deriziotis et al. (2014) demonstrated that TBR1 forms homodimers and interacts with FOXP2 (605317) most likely through the T-box domain. Mutations in the FOXP2 gene, which cause a speech-language disorder (SPCH1; 602081), were found to interrupt the interaction with TBR1.

Den Hoed et al. (2018) demonstrated that TBR1 interacts with the long isoform of BCL11A (606557).

In a review of published literature, Vegas et al. (2018) noted that TBR1 has an established role in patterning of the central nervous system, including regulation of laminar and regional neuronal identities during cortical development. It is part of the PAX6 (607108)-TBR2 (604615)-NEUROD (601724)-TBR1 transcription factor cascade that is critical for controlling glutamatergic neuronal cell fate in the cortex, cerebellum, and hippocampus. By interacting with CASK and FOX2P, TBR1 regulates several genes, including GRIN2B (138252) and RELN (600514), which are necessary for proper neuronal migration during corticogenesis. All of these genes have been reported to be mutated in various forms of intellectual disability, autism, and malformations of cortical development, suggesting a common pathway.


Mapping

By linkage analysis with a mouse mapping panel, Bulfone et al. (1995) mapped the Tbr1 gene to chromosome 2. By homology of synteny, the human TBR1 gene is predicted to map to chromosome 2q23-q37.

Gross (2019) mapped the TBR1 gene to chromosome 2q24.2 based on an alignment of the TBR1 sequence (GenBank BC104844) with the genomic sequence (GRCh38).


Molecular Genetics

In 4 unrelated patients with impaired intellectual development with autism and speech delay (IDDAS; 606053), Deriziotis et al. (2014) identified 4 different de novo heterozygous mutations in the TBR1 gene (604616.0001-604616.0004). There were 2 frameshift mutations, resulting in premature termination, and 2 missense mutations at highly conserved residues in the T-box domain. In vitro functional expression studies using cellular transfection models (HEK293 cells and SHSY5Y neuroblastoma cells) showed that the frameshift mutations resulted in nonfunctional proteins that lost nuclear localization, lost the interaction with CASK and FOXP2, and had deficient transcriptional repression activity compared to wildtype. Furthermore, these mutations may have resulted in nonsense-mediated mRNA decay, but patient tissue was not available for study. The findings related to these mutations were consistent with haploinsufficiency. Similar in vitro studies of the missense variants showed that they retained some transcriptional repression activity, suggesting that DNA-binding activity was not completely abolished, although they were unable to interact with FOXP2. These variants were able to interact with CASK and homodimerize with wildtype TBR1 to form abnormal aggregates in the nucleus. The findings related to these mutations suggested a dominant-negative effect. The patients carrying loss-of-function mutations had more severe cognitive impairment than those with missense mutations. Several additional missense variants were found in patients that had been inherited from unaffected parents. Functional studies of the inherited variants showed that they had little or no impact on TBR1 function, suggesting that inherited TBR1 mutations do not have a role in autism, although minor contributions in conjunction with additional unidentified variants in other genes could not be excluded. The study also suggested that disruption of TBR1-FOXP2 interactions, caused by mutations in either gene, result in speech and language deficits, thus providing a mechanistic bridge between neurodevelopmental disorders.

In 2 unrelated patients with IDDAS, den Hoed et al. (2018) identified de novo heterozygous mutations in the TBR1 gene that affected conserved residues in the T-box domain (604616.0005 and 604616.0006). In vitro functional expression studies in HEK293 cells showed that these mutant proteins retained the ability to repress luciferase activity, were able form homodimers with TBR1, and colocalized with CASK, but formed abnormal aggregates in the nucleus, suggesting a dominant-negative effect. The mutations abolished the TBR1-FOXP2 (605317) interaction.

In 2 unrelated patients with IDDAS, McDermott et al. (2018) identified de novo heterozygous mutations in the TBR1 gene (G316X and L311P). Functional studies of the variants were not performed.

In 2 unrelated boys with IDDAS, Vegas et al. (2018) identified the same de novo heterozygous frameshift mutation in the TBR1 gene (604616.0007). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the mutation may lead to disruption of the downstream RELN pathway. Both patients had malformations of cortical development, including pachygyria, on brain imaging, thus expanding the phenotype associated with TBR1 mutations.


Animal Model

Hevner et al. (2001) developed mice with targeted disruption of the Tbr1 gene. Mutant mice died shortly after birth in the absence of hand feeding. The cortex of neonatal mutants was approximately normal size, but early-born neurons, which guide early neuronal migrations and axonal projections, showed molecular and functional defects. Early-born cells formed a preplate but did not express markers of Cajal-Retzius, subplate, or layer 6 neurons. Cajal-Retzius cells expressed decreased levels of reelin (600514), resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. Markers of later-born cortical layers were relatively normal, and other properties of cortical neurons, such as neurotransmitter expression, cell death, and neuronal morphology, were mostly unaffected.

Huang et al. (2014) showed that haploinsufficiency of Tbr1 in mice resulted in features of autism, including impaired social interaction, impaired vocalization, and impaired cognition and memory. Examination of the brain from Tbr1 +/- mice showed defective axonal projection of neurons in the amygdala. Tbr-null mice had severely impaired neuronal migration in the cerebral cortex.

Fazel Darbandi et al. (2018) generated mice with conditional Tbr1 deletion during late gestation in cortical layer-6 neurons. Gene expression analysis of wildtype and mutant mice demonstrated that late gestational/neonatal Tbr1 expression maintained layer-6 identity in postnatal cortex. Tbr1 directly controlled transcription of genes that define the molecular properties of layer-6 pyramidal neurons and functioned as an activator or repressor. Examination of corticothalamic projections in mutant mice showed that, after about embryonic day 17.5, Tbr1 was required for maturation of corticothalamic connectivity, preferentially in anterior and anteromedial thalamus. Mutant mice exhibited synaptic deficits with reduced number of excitatory synapses, altered cortical interneuron lamination, and reduced inhibitory synaptic density. Restoring expression of Wnt7b (601967), which was dysregulated in mutant mouse neurons, rescued the synaptic deficits of mutant mice. Hyperpolarization-activated cation currents were increased in both heterozygous and homozygous Tbr1 mutant mice. Behavioral analysis showed that neonatal Tbr1 deletion in layer-6 neurons led to increased anxiety-like behavior in heterozygotes and increased aggressive behavior in homozygous mutants.


ALLELIC VARIANTS 7 Selected Examples):

.0001   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, 1-BP DEL, C
SNP: rs1684130791, ClinVar: RCV000735639

In a 7-year-old boy (11480.p1) with impaired intellectual development and autism (IDDAS; 606053), Deriziotis et al. (2014) identified a de novo heterozygous 1-bp deletion in the TBR1 gene (chr2.162,273,322delC, GRCh37), resulting in frameshift and premature termination (Ala136ProfsTer80), and predicted to result in a protein lacking the functional T-box domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) reported that this patient had a verbal IQ of 24, nonverbal IQ of 41, and was nonverbal at the time of the report; language delay and language regression were also noted. Cellular transfection studies of the mutation showed that a truncated protein was expressed at higher levels compared to wildtype, but had aberrant subcellular localization with diffuse distribution in the cytoplasm and only some nuclear localization. In addition, the mutant protein lost its transcriptional repressive ability in a luciferase assay, interrupted the TBR1 interaction with CASK (300172), abolished the interaction with FOXP2 (605317), and was unable to form homodimers with wildtype TBR1. Deriziotis et al. (2014) noted that the mutation may have resulted in nonsense-mediated mRNA decay, but patient cells were not available. The findings were consistent with haploinsufficiency.


.0002   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, 1-BP INS, C
SNP: rs1684180699, ClinVar: RCV000735640

In an 8-year-old girl (13796.p1) with intellectual disability and autism (IDDAS; 606053), Deriziotis et al. (2014) identified a de novo heterozygous 1-bp insertion in the TBR1 gene (chr2.162,275,481insC, GRCh37) resulting in a ser351-to-ter (S351X) substitution predicted to result in a protein lacking the functional T-box domain. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) reported that this patient had a verbal IQ of 69, nonverbal IQ of 63, and had phrase speech at the time of the report; language delay without language regression was also noted. Cellular transfection of the mutant showed that a truncated protein was expressed at lower levels compared to wildtype, but had aberrant subcellular localization with diffuse distribution in the cytoplasm and formation of large aggregates. In addition, the mutant protein lost its transcriptional repressive ability in a luciferase assay, interrupted the TBR1 interaction with CASK (300172), abolished the interaction with FOXP2 (605317), and was unable to form homodimers with wildtype TBR1. Deriziotis et al. (2014) noted that the mutation may have resulted in nonsense-mediated mRNA decay, but patient cells were not available. The findings were consistent with haploinsufficiency.


.0003   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, LYS228GLU
SNP: rs1553510219, ClinVar: RCV000735641

In a 7-year-old boy (13814.p1) with intellectual disability and autism (IDDAS; 606053), Deriziotis et al. (2014) identified a de novo heterozygous A-to-G transition in the TBR1 gene (chr2.162,273,603A-G, GRCh37), resulting in a lys228-to-glu (K228E) substitution at a highly conserved residue in the T-box domain, which is involved in DNA binding and protein-protein interactions. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) reported that this patient had a verbal IQ of 75, nonverbal IQ of 78, and was verbally fluent at the time of the report; language delay without language regression was also noted. The patient had also been diagnosed with developmental coordination disorder. Cellular transfection of the mutant protein showed that it was imported into the nucleus, but formed abnormal aggregates. The mutant protein partially lost its transcriptional repressive ability in a luciferase assay, suggesting retention of partial DNA-binding capacity. The mutant protein retained the ability to homodimerize with wildtype TBR1 and to interact with CASK (300173), suggesting a dominant-negative effect, but was unable to interact with FOXP2 (605317).


.0004   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, ASN374HIS
SNP: rs1684182454, ClinVar: RCV000735642

In a patient (09C86232A) with mild cognitive impairment and autism spectrum disorder (IDDAS; 606053), Deriziotis et al. (2014) reported a de novo heterozygous A-to-C transversion (chr2.162,275,553A-C, GRCh37) in the TBR1 gene, resulting in an asn374-to-his (N374H) substitution at a highly conserved residue in the T-box domain, which is involved in DNA binding and protein-protein interactions. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project database. Deriziotis et al. (2014) stated that this patient had a nonverbal IQ of 74. In vitro cellular expression studies showed that the mutant protein was imported into the nucleus, but formed abnormal aggregates. The mutant protein only partially lost its transcriptional repressive ability in a luciferase assay, suggesting retention of partial DNA-binding capacity. The mutant protein retained the ability to homodimerize with wildtype TBR1 and to interact with CASK (300173), suggesting a dominant-negative effect, but was unable to interact with FOXP2 (605317).


.0005   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, TRP271CYS
SNP: rs1559060428, ClinVar: RCV000735643

In a patient (09C86693) with autism and intellectual disability (IDDAS; 606053), den Hoed et al. (2018) reported a de novo heterozygous c.813G-T transversion (c.813G-T, NM_006593) in the TBR1 gene, resulting in a typ271-to-cys (W271C) substitution. The patient was from a large cohort of individuals with autism who underwent exome sequencing. Den Hoed et al. (2018) noted that the W271C mutation occurs in the T-box domain. Using in vitro functional expression studies in HEK293 cells, den Hoed et al. (2018) showed that the mutant W271C protein retained the ability to repress luciferase activity, but was able to form homodimers with TBR1 and colocalized with CASK in the nucleus to form abnormal aggregates, suggesting a dominant-negative effect. The mutation also abolished the TBR1-FOXP2 (605317) interaction. A different variant affecting the same residue (W271R) was identified in another patient, but functional studies did not show significant adverse effects on TBR1 function. The mutant protein also showed greater stability compared to wildtype TBR1.


.0006   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, LYS389GLU
SNP: rs1553510677, ClinVar: RCV000735644

In a patient (220-9833-201) with autism and intellectual disability (IDDAS; 606053), den Hoed et al. (2018) reported a de novo heterozygous c.1165A-G transition (c.1165A-G, NM_006593) in the TBR1 gene, resulting in a lys389-to-glu (K389E) substitution in the T-box domain. In vitro functional expression studies in HEK293 cells showed that the mutant protein retained the ability to repress luciferase activity, was able form homodimers with TBR1, and colocalized with CASK, but formed abnormal aggregates in the nucleus, suggesting a dominant-negative effect. The mutation abolished the TBR1-FOXP2 (605317) interaction. The mutant protein also showed greater stability compared to wildtype TBR1.


.0007   INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

TBR1, 7-BP DUP, NT1588
SNP: rs869312704, ClinVar: RCV000209932, RCV000505228, RCV000509230, RCV000627109, RCV000627110, RCV000627111, RCV000735645, RCV000824817, RCV001200907, RCV001200914, RCV001200915, RCV001266838, RCV002515568

In 2 unrelated boys with intellectual disability and autism (IDDAS; 606053), Vegas et al. (2018) identified the same de novo heterozygous 7-bp duplication (c.1588_1594dup, NM_006593.3) in exon 6 of the TBR1 gene, resulting in a frameshift and premature termination (Thr532ArgfsTer144) in the CASK (300172)-interacting domain. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the mutation may lead to disruption of the downstream RELN pathway (see 600514). Both patients had malformations of cortical development, including pachygyria, on brain imaging, thus expanding the phenotype associated with TBR1 mutations.


REFERENCES

  1. Bulfone, A., Smiga, S. M., Shimamura, K., Peterson, A., Puelles, L., Rubenstein, J. L. R. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15: 63-78, 1995. [PubMed: 7619531] [Full Text: https://doi.org/10.1016/0896-6273(95)90065-9]

  2. den Hoed, J., Sollis, E., Venselaar, H., Estruch, S. B., Deriziotis, P., Fisher, S. E. Functional characterization of TBR1 variants in neurodevelopmental disorder. Sci. Rep. 8: 14279, 2018. [PubMed: 30250039] [Full Text: https://doi.org/10.1038/s41598-018-32053-6]

  3. Deriziotis, P., O'Roak, B. J., Graham, S. A., Estruch, S. B., Dimitropoulou, D., Bernier, R. A., Gerdts, J., Shendure, J., Eichler, E. E., Fisher, S. E. De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature Commun. 5: 4954, 2014. Note: Electronic Article. [PubMed: 25232744] [Full Text: https://doi.org/10.1038/ncomms5954]

  4. Fazel Darbandi, S., Robinson Schwartz, S. E., Qi, Q., Catta-Preta, R., Pai, E. L.-L., Mandell, J. D., Everitt, A., Rubin, A., Krasnoff, R. A., Katzman, S., Tastad, D., Nord, A. S., Willsey, A. J., Chen, B., State, M. W., Sohal, V. S., Rubenstein, J. L. R. Neonatal Tbr1 dosage controls cortical layer 6 connectivity. Neuron 100: 831-845, 2018. [PubMed: 30318412] [Full Text: https://doi.org/10.1016/j.neuron.2018.09.027]

  5. Gross, M. B. Personal Communication. Baltimore, Md. 4/23/2019.

  6. Hevner, R. F., Shi, L., Justice, N., Hsueh, Y.-P., Sheng, M., Smiga, S., Bulfone, A., Goffinet, A. M., Campagnoni, A. T., Rubenstein, J. L. R. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29: 353-366, 2001. [PubMed: 11239428] [Full Text: https://doi.org/10.1016/s0896-6273(01)00211-2]

  7. Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M. Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002. [PubMed: 10749215] [Full Text: https://doi.org/10.1038/35005118]

  8. Huang, T.-N., Chuang, H.-C., Chou, W.-H., Chen, C.-Y., Wang, H.-F., Chou, S.-J., Hsueh, Y.-P. Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nature Neurosci. 17: 240-247, 2014. [PubMed: 24441682] [Full Text: https://doi.org/10.1038/nn.3626]

  9. McDermott, J. H., DDD Study, Clayton-Smith, J., Briggs, T. A. The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum. Europ. J. Med. Genet. 61: 253-256, 2018. [PubMed: 29288087] [Full Text: https://doi.org/10.1016/j.ejmg.2017.12.009]

  10. Ueno, M., Kimura, N., Nakashima, K., Saito-Ohara, F., Inazawa, J., Taga, T. Genomic organization, sequence and chromosomal localization of the mouse Tbr2 gene and a comparative study with Tbr1. Gene 254: 29-35, 2000. [PubMed: 10974533] [Full Text: https://doi.org/10.1016/s0378-1119(00)00290-0]

  11. Vegas, N., Cavallin, M., Kleefstra, T., de Boer, L., Philbert, M., Maillard, C., Boddaert, N., Munnich, A., Hubert, L., Bery, A., Besmond, C., Bahi-Buisson, N. Mutations in TBR1 gene leads to cortical malformations and intellectual disability. Europ. J. Med. Genet. 61: 759-764, 2018. [PubMed: 30268909] [Full Text: https://doi.org/10.1016/j.ejmg.2018.09.012]


Contributors:
Matthew B. Gross - updated : 04/23/2019
Bao Lige - updated : 02/13/2019
Cassandra L. Kniffin - updated : 12/07/2018
Patricia A. Hartz - updated : 7/8/2003
Patricia A. Hartz - updated : 4/29/2002
Ada Hamosh - updated : 3/28/2000

Creation Date:
Paul J. Converse : 2/25/2000

Edit History:
alopez : 02/28/2022
mgross : 04/23/2019
mgross : 02/13/2019
mgross : 02/13/2019
carol : 02/11/2019
alopez : 01/02/2019
alopez : 12/19/2018
alopez : 12/19/2018
alopez : 12/19/2018
alopez : 12/19/2018
ckniffin : 12/07/2018
terry : 07/27/2012
mgross : 7/8/2003
carol : 4/30/2002
terry : 4/29/2002
carol : 3/28/2000
carol : 2/28/2000