Human Gene Module / Chromosome 17 / THRA

THRAthyroid hormone receptor alpha

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
3 / 0
Aliases
THRA, AR7,  CHNG6,  EAR7,  ERB-T-1,  ERBA,  ERBA1,  NR1A1,  THRA1,  THRA2,  c-ERBA-1
Associated Syndromes
-
Chromosome Band
17q21.1
Associated Disorders
-
Relevance to Autism

Mice with a mutated version of the thyroid hormone receptor alpha displayed a depressive and anxious phenotype that was alleviated with continuous T3-substitution therapy (Pilhatsch et al., 2010).

Molecular Function

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to THRA (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Increased depressive behaviour in mice harboring the mutant thyroid hormone receptor alpha 1 Pilhatsch M , et al. (2010) No -
2 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
3 Support Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients Kalikiri MK , et al. (2017) Yes -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1150C>T p.Arg384Cys missense_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.54-1G>A - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1280dup p.Ala428GlyfsTer8 frameshift_variant Familial Maternal - 31452935 Feliciano P et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Mice with a mutated version of the thyroid hormone receptor alpha displayed a depressive and anxious phenotype that was alleviated with continuous T3-substitution therapy (Pilhatsch et al., 2010). A de novo missense variant that was predicted to be damaging by at least 2 of 5 algorithms (SIFT, PolyPhen2, Mutation Assessor, CADD, PhyloP) was identified in one of two affected siblings (-03) from a multiplex ASD family (1-0273) in Yuen et al., 2015. Potentially deleterious missense variants in the ligand binding domain of the THRA gene were identified in Indian ASD probands in Kalikiri et al., 2017.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Mice with a mutated version of the thyroid hormone receptor alpha displayed a depressive and anxious phenotype that was alleviated with continuous T3-substitution therapy (Pilhatsch et al., 2010). A de novo missense variant that was predicted to be damaging by at least 2 of 5 algorithms (SIFT, PolyPhen2, Mutation Assessor, CADD, PhyloP) was identified in one of two affected siblings (-03) from a multiplex ASD family (1-0273) in Yuen et al., 2015. Potentially deleterious missense variants in the ligand binding domain of the THRA gene were identified in Indian ASD probands in Kalikiri et al., 2017.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Mice with a mutated version of the thyroid hormone receptor alpha displayed a depressive and anxious phenotype that was alleviated with continuous T3-substitution therapy (Pilhatsch et al., 2010). A de novo missense variant that was predicted to be damaging by at least 2 of 5 algorithms (SIFT, PolyPhen2, Mutation Assessor, CADD, PhyloP) was identified in one of two affected siblings (-03) from a multiplex ASD family (1-0273) in Yuen et al., 2015. Potentially deleterious missense variants in the ligand binding domain of the THRA gene were identified in Indian ASD probands in Kalikiri et al., 2017.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Mice with a mutated version of the thyroid hormone receptor alpha displayed a depressive and anxious phenotype that was alleviated with continuous T3-substitution therapy (Pilhatsch et al., 2010). A de novo missense variant that was predicted to be damaging by at least 2 of 5 algorithms (SIFT, PolyPhen2, Mutation Assessor, CADD, PhyloP) was identified in one of two affected siblings (-03) from a multiplex ASD family (1-0273) in Yuen et al., 2015. Potentially deleterious missense variants in the ligand binding domain of the THRA gene were identified in Indian ASD probands in Kalikiri et al., 2017.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2018
icon
4

Increased from to 4

Description

Mice with a mutated version of the thyroid hormone receptor alpha displayed a depressive and anxious phenotype that was alleviated with continuous T3-substitution therapy (Pilhatsch et al., 2010). A de novo missense variant that was predicted to be damaging by at least 2 of 5 algorithms (SIFT, PolyPhen2, Mutation Assessor, CADD, PhyloP) was identified in one of two affected siblings (-03) from a multiplex ASD family (1-0273) in Yuen et al., 2015. Potentially deleterious missense variants in the ligand binding domain of the THRA gene were identified in Indian ASD probands in Kalikiri et al., 2017.

Krishnan Probability Score

Score 0.58994042954613

Ranking 485/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.16700676973139

Ranking 7258/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.854282768868

Ranking 3620/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.42926924814681

Ranking 1128/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
A2ML1 Alpha-2-macroglobulin-like protein 1 Human Protein Binding 144568 A8K2U0
HAL Histidine ammonia-lyase Human Protein Binding 3034 P42357
Submit New Gene

Report an Error