Human Gene Module / Chromosome 17 / NR1D1

NR1D1nuclear receptor subfamily 1 group D member 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
7 / 0
Aliases
NR1D1, EAR1,  THRA1,  THRAL,  ear-1,  hRev
Associated Syndromes
-
Chromosome Band
17q21.1
Associated Disorders
-
Relevance to Autism

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Molecular Function

This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NR1D1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erb? Jager J , et al. (2014) No -
2 Primary Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients Yang Z , et al. (2015) Yes -
3 Recent Recommendation Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders Goto M , et al. (2017) Yes -
4 Support - Zhou X et al. (2022) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.747C>A p.Pro249= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1153G>A p.Gly385Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.233A>G p.Asp78Gly missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1499G>A p.Arg500His missense_variant De novo - Multiplex 28262759 Goto M , et al. (2017)
c.58A>C p.Ser20Arg missense_variant Familial Paternal Simplex 25957987 Yang Z , et al. (2015)
c.1012C>T p.Pro338Ser missense_variant Familial Maternal Multiplex 28262759 Goto M , et al. (2017)
c.1031A>C p.Asn344Thr missense_variant Familial Maternal Multiplex 28262759 Goto M , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

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

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Reports Added
[New Scoring Scheme]
4/1/2017
icon
4

Increased from to 4

Description

Screening of circadian-relevant genes in Japanese ASD patients with or without sleep disorders identified a missense variant in the NR1D1 gene (Yang et al., 2016). Additional screening of Caucasian ASD patients for NR1D1 variants identified several novel missense variants, including a de novo missense variant that failed to rescue defects in the positioning of cortical neurons in the embryonic mouse brain following RNAi-mediated knockdown of endogeneous Nr1d1 (Goto et al., 2017). However, NR1D1 variants identified in these two studies showed incomplete segregation with ASD. Nr1d1-knockout mice were shown to display hyperactivity, impaired response habituation in novel environments, deficiencies in contextual memories, and impaired nest-building activity, suggesting impaired hippocampal function (Jager et al., 2014).

Krishnan Probability Score

Score 0.51276314846167

Ranking 1801/25841 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 0.9460854182801

Ranking 2755/18225 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 0.93729120576235

Ranking 13476/18665 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 -0.060009392658952

Ranking 10788/20870 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
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