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Relevance to Autism

Smith-Magenis syndrome is caused either by large interstitial deletions in the 17p11.2 chromosomal region (Smith et al., 1986) or by mutations in the RAI1 gene (Slager et al., 2003), which is located within the Smith-Magenis chromosomal region. Conversely, Potocki-Lupski syndrome is caused by duplications of the same 17p11.2 chromosomal region (Potocki et al., 2007). Both syndromes share overlapping clinical features, including behavioral problems such as autistic features. RAI1 was included within a 17p11.2 duplication identified in an individual with autism and intellectual disability and showed altered gene expression (Nakamine et al., 2008); it was identified as the single gene in this interval that overlaps with the region affected in Potocki-Lupski syndrome, making it those most likely candidate. A de novo frameshift variant was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo missense variants (one of which was predicted to be damaging in silico) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). A de novo protein-truncating variant in RAI1 was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; three protein-truncating variants in this gene were also observed in case samples from the Danish iPSYCH study in this report. Furthermore, TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified RAI1 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo missense variant in the RAI1 gene that was experimentally shown to significantly reduce BDNF-enhancer-driven transcription activity was identified in a male patient diagnosed with ASD and displaying an atypical Smith-Magenis syndrome presentation in Abad et al., 2018. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified RAI1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Transcriptional regulator of the circadian clock components: CLOCK, BMAL1, BMAL2, PER1/3, CRY1/2, NR1D1/2 and RORA/C. Positively regulates the transcriptional activity of CLOCK a core component of the circadian clock. Regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. May be important for embryonic and postnatal development. May be involved in neuronal differentiation.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay.
ASD
Positive Association
Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G)
ASD
Support
Complex Diagnostics of Non-Specific Intellectual Developmental Disorder
DD, ID
Support
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
ID
Support
Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
A unique Smith-Magenis patient with a de novo intragenic deletion on the maternally inherited overexpressed RAI1 allele
Smith-Magenis syndrome, DD, ID
Stereotypy
Support
Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA recep...
DD, ID
Hypoglycemia, lactic acidosis
Support
ASD
DD, ID, epilepsy/seizures
Support
A Rare De Novo RAI1 Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome ...
ASD
Support
Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders
ASD
ADHD, DD, ID
Support
Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...
ASD
ID, epilepsy
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID
Behavioral disorder (including stereotypies)
Support
Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith-Magenis syndrome
Smith-Magenis syndrome
Support
Gene-network analysis identifies susceptibility genes related to glycobiology in autism.
ASD
Support
Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome
Smith-Magenis syndrome
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Support
Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism
ASD
Support
Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings
ASD
Support
Loss of Rai1 enhances hippocampal excitability and epileptogenesis in mouse models of Smith-Magenis syndrome
Smith-Magenis syndrome
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
ASD, ADHD, DD
Support
RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling
Support
Integrating de novo and inherited variants in 42
ASD
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders
DD, ID
Support
Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy
ASD
Highly Cited
Interstitial deletion of (17)(p11.2p11.2) in nine patients.
Smith-Magenis syndrome
Highly Cited
Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism...
Potocki-Lupski syndrome
Highly Cited
Mutations in RAI1 associated with Smith-Magenis syndrome.
Smith-Magenis syndrome
Recent Recommendation
How much is too much? Phenotypic consequences of Rai1 overexpression in mice.
Recent Recommendation
Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome.
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.
Recent Recommendation
Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in ...
Potocki-Lupski syndrome
Recent Recommendation
Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage sensitive loci also associated...
Smith-Magenis syndrome
Recent Recommendation
Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice.
Recent Recommendation
Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN208R001 
 copy_number_gain 
  
  
 De novo 
  
  
 GEN208R002 
 copy_number_loss 
  
  
  
  
  
 GEN208R003 
 copy_number_gain 
  
  
  
  
  
 GEN208R004 
 missense_variant 
 c.1148C>T 
 p.Pro383Leu 
 Unknown 
  
 Unknown 
 GEN208R005 
 missense_variant 
 c.4238T>C 
 p.Met1413Thr 
 Unknown 
  
 Unknown 
 GEN208R006 
 missense_variant 
 c.1471G>A 
 p.Glu491Lys 
 De novo 
  
 Unknown 
 GEN208R007 
 frameshift_variant 
 c.2332_2336del 
 p.Gly778GlnfsTer7 
 De novo 
  
 Simplex 
 GEN208R008 
 frameshift_variant 
 c.3575del 
 p.Ser1192ThrfsTer8 
 De novo 
  
 Simplex 
 GEN208R009 
 missense_variant 
 c.1664C>T 
 p.Thr555Ile 
 De novo 
  
  
 GEN208R010 
 missense_variant 
 c.2347G>A 
 p.Asp783Asn 
 De novo 
  
  
 GEN208R011 
 frameshift_variant 
 c.2966_2969del 
 p.Lys989SerfsTer74 
 De novo 
  
  
 GEN208R012 
 missense_variant 
 c.3440G>A 
 p.Arg1147Gln 
 De novo 
  
 Simplex 
 GEN208R013 
 stop_gained 
 c.2273G>A 
 p.Trp758Ter 
 De novo 
  
  
 GEN208R014 
 frameshift_variant 
 c.412del 
 p.Val138TrpfsTer8 
 De novo 
  
 Simplex 
 GEN208R015 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN208R016 
 missense_variant 
 c.304G>A 
 p.Val102Ile 
 Familial 
 Maternal 
  
 GEN208R017 
 frameshift_variant 
 c.1854del 
 p.Ile618MetfsTer201 
 De novo 
  
  
 GEN208R018 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN208R019 
 missense_variant 
 c.629C>G 
 p.Pro210Arg 
 De novo 
  
 Simplex 
 GEN208R020 
 missense_variant 
 c.3649C>T 
 p.Arg1217Trp 
 De novo 
  
  
 GEN208R021 
 stop_gained 
 c.4678C>T 
 p.Arg1560Ter 
 De novo 
  
  
 GEN208R022 
 synonymous_variant 
 c.4710C>T 
 p.Pro1570%3D 
 De novo 
  
  
 GEN208R023 
 frameshift_variant 
 c.2879del 
 p.Arg960GlnfsTer104 
 De novo 
  
  
 GEN208R024 
 frameshift_variant 
 c.4342dup 
 p.Ser1448LysfsTer42 
 De novo 
  
  
 GEN208R025 
 splice_site_variant 
 c.5566-1G>C 
  
 De novo 
  
  
 GEN208R026 
 stop_gained 
 c.3265C>T 
 p.Arg1089Ter 
 De novo 
  
 Simplex 
 GEN208R027 
 stop_gained 
 c.3265C>T 
 p.Arg1089Ter 
 De novo 
  
 Simplex 
 GEN208R028 
 missense_variant 
 c.3130C>T 
 p.Pro1044Ser 
 Unknown 
  
 Simplex 
 GEN208R029 
 missense_variant 
 c.422A>T 
 p.Tyr141Phe 
 Unknown 
  
 Simplex 
 GEN208R030 
 frameshift_variant 
 c.2526_2545del 
 p.His843LeufsTer19 
 De novo 
  
  
 GEN208R031 
 stop_gained 
 c.13C>T 
 p.Arg5Ter 
 De novo 
  
  
 GEN208R032 
 frameshift_variant 
 c.1069_1070insC 
 p.Ser357ThrfsTer32 
 De novo 
  
  
 GEN208R033 
 missense_variant 
 c.223G>A 
 p.Ala75Thr 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
17
Deletion-Duplication
 67
  construct
17
Duplication
 8
 
17
Duplication
 1
 
17
Duplication
 1
 
17
Duplication
 3
 
17
Duplication
 1
 
17
Duplication
 4
 
17
Duplication
 1
 

Model Summary

Rai1 haploinsufficiency is responsible for obesity and craniofacial phenotypes in mice with Smith Magenis Syndrome deletions, and indicate Rai1 is important for embryonic and postnatal developments.

References

Type
Title
Author, Year
Primary
Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome.
Primary
Circadian abnormalities in mouse models of Smith-Magenis syndrome: evidence for involvement of RAI1.
Additional
Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted insertion of lacZ coding sequence into exon 2 of Rai1 gene encoding residues 537-1790.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57BL/6
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Skeletal development1
Increased
 Histology
 3-6.5 weeks
Skeletal development: craniofacial1
Increased
 Histology
 3-6.5 weeks
Mortality/lethality1
Increased
 General observations
 E15.5
Skeletal development1
Increased
 General observations
 Unreported
Skeletal development1
Increased
 Histology
 3-6.5 weeks
General characteristics1
 No change
 General observations
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
BDNF brain-derived neurotrophic factor 627 P23560 ChIP; Luciferase reporter assay
Burns B , et al. 2010
CHD8 chromodomain helicase DNA binding protein 8 57680 Q9HCK8 ChIP-chip
Subtil-Rodrguez A , et al. 2013
DDIT3 DNA-damage-inducible transcript 3 1649 P35638 M2H
Ravasi T , et al. 2010
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
GATA1 GATA binding protein 1 (globin transcription factor 1) 2623 P15976 M2H
Ravasi T , et al. 2010
GLI1 GLI family zinc finger 1 2735 P08151 M2H
Ravasi T , et al. 2010
LZTR1 leucine-zipper-like transcription regulator 1 8216 Q8N653 M2H
Ravasi T , et al. 2010
MAML3 mastermind-like 3 (Drosophila) 55534 Q96JK9 M2H
Ravasi T , et al. 2010
NAGK N-acetylglucosamine kinase 55577 Q9UJ70 IP; LC-MS/MS
Huttlin EL , et al. 2015
PIN1 peptidylprolyl cis/trans isomerase, NIMA-interacting 1 5300 Q13526 Y2H; Histone lysine methyltransferase (HKMT) assay
Rual JF , et al. 2005
PIN1 peptidylprolyl cis/trans isomerase, NIMA-interacting 1 5300 Q13526 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
TESC tescalcin 54997 Q96BS2 Y2H; Histone lysine methyltransferase (HKMT) assay
Rual JF , et al. 2005
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013
XRN2 5'-3' exoribonuclease Dhp1 2542674 P40848 X-ray crystallography; Exoribonuclease assay
Xiang S , et al. 2009
ZNF496 zinc finger protein 496 84838 Q96IT1 M2H
Ravasi T , et al. 2010

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