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RAI1
retinoic acid induced 1
The RAI1 gene provides instructions for a protein that acts as a transcription factor, playing a critical role in brain development and regulating circadian rhythms. The RAI1 gene is responsible for producing the retinoic acid induced 1 protein, which functions as a transcription factor in neurons.
RAI1 is located on the short (p) arm of chromosome 17, at band 17p11.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 17 in the library →Overview
The RAI1 gene, also known as retinoic acid induced 1, encodes a protein crucial for various developmental processes, particularly within the nervous system. As a transcription factor, the RAI1 protein controls the activity of other genes by binding to DNA, influencing their expression levels. Research indicates its significant involvement in early brain development, the regulation of circadian rhythms, and the formation of craniofacial bones.
Dysregulation of the RAI1 gene is associated with several neurodevelopmental disorders. Inherited in an autosomal dominant manner, alterations in RAI1 can lead to conditions characterised by intellectual disabilities, developmental delays, and distinct physical features.
What the gene does
The RAI1 protein functions primarily as a transcription factor, meaning it regulates the expression of other genes by binding to specific DNA sequences. This regulatory role is particularly important in nerve cells (neurons) within the brain, where the protein is highly active. The RAI1 protein influences the transcription of genes that are vital for early brain development, contributing to the proper formation and function of neural structures.
Beyond brain development, studies suggest that RAI1 also plays a part in regulating genes involved in circadian rhythms, which are the natural, internal processes that regulate the sleep-wake cycle and other daily patterns. Furthermore, the protein appears to be implicated in the development of bones in the head and face, known as craniofacial bones, highlighting its broad developmental impact.
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Chromosome location
The RAI1 gene is situated on chromosome 17 at position 17p11.2. This specific location refers to the short (p) arm of chromosome 17, within region 1, band 1, sub-band 2. The precise genomic coordinates are important for understanding the context of gene duplications or deletions that can affect RAI1 function.
Protein structure
The RAI1 protein comprises 1906 amino acids and features a complex domain architecture essential for its function as a transcription factor. It contains several large disordered regions, including segments spanning amino acids 1-261, 273-299, 335-370, 469-520, 538-571, 656-712, 937-1299, 1344-1570, 1613-1637, and 1746-1775. These disordered regions often play roles in protein-protein interactions and flexible binding.
Within the protein, there are also two nuclear localisation signals (NLS) motifs, located at amino acids 1160-1177 and 1223-1240, which are crucial for directing the protein to the cell nucleus where it performs its transcriptional regulatory functions. Towards the C-terminus, two distinct zinc finger domains are present: a C2HC pre-PHD-type zinc finger at amino acids 1780-1835 and a PHD-type zinc finger at amino acids 1855-1903. An additional disordered region (1794-1819) overlaps with the C2HC pre-PHD-type zinc finger. Zinc finger domains are typically involved in DNA binding and protein-protein interactions, supporting RAI1's role as a transcription factor.
Key variants
Genetic variants within the RAI1 gene can significantly impact its function, leading to various health conditions. These variants include deletions, duplications, and smaller changes such as point mutations. Pathogenic or likely pathogenic variants can either reduce the amount of functional RAI1 protein produced or alter its structure, thereby impairing its ability to regulate gene expression. The specific type and location of a variant can influence the severity and presentation of associated disorders. Genetic testing can identify these variants, aiding in diagnosis and management.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.13C>T | p.Arg5Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Smith-Magenis syndrome |
c.1810C>T | p.Gln604Ter | Pathogenic | ★★☆☆ | RAI1-related disorder |
c.238C>T | p.Arg80Ter | Pathogenic | ★★☆☆ | not provided |
c.2396dup | p.Gly800fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2763_2764del | p.Glu923fs | Pathogenic/Likely pathogenic | ★★☆☆ | Smith-Magenis syndrome |
c.2966_2969del | p.Lys989fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.3103dup | p.Gln1035fs | Pathogenic | ★★☆☆ | Smith-Magenis syndrome |
c.3265C>T | p.Arg1089Ter | Pathogenic | ★★☆☆ | not provided |
c.4678C>T | p.Arg1560Ter | Pathogenic | ★★☆☆ | not provided |
c.4681C>T | p.Arg1561Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Smith-Magenis syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the RAI1 gene are primarily associated with neurodevelopmental disorders. The gene's critical role in brain development means that alterations can lead to conditions characterised by intellectual disability, developmental delays, and distinctive physical and behavioural features. One significant condition linked to RAI1 variants is Smith-Magenis syndrome, which often results from a partial or total loss of RAI1 function. Duplications of the RAI1 gene are also implicated in other conditions such as Potocki-Lupski syndrome and Yuan-Harel-Lupski syndrome, both characterised by developmental delays, intellectual disabilities, and behavioural issues.
Inheritance pattern
Conditions caused by pathogenic RAI1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the RAI1 gene is recognised within several NHS Genomic Medicine Service pathways due to its clinical significance. It holds a 'green' status on the DDG2P panel, indicating strong evidence for its involvement in developmental disorders. Furthermore, RAI1 is green-rated on the Foetal Anomalies (R21) and Intellectual Disability panels, underscoring its established role in these conditions and its importance for diagnostic screening within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that generally healthy lifestyle choices, such as a balanced diet and regular physical activity, support overall well-being. Maintaining a consistent sleep schedule may be particularly helpful for individuals with conditions affecting circadian rhythms, including those potentially linked to RAI1 gene function. However, specific lifestyle interventions to prevent or treat conditions associated with RAI1 variants are not established.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions associated with RAI1 gene variants. Individuals considering any supplement for health purposes should consult with a healthcare professional to ensure it is appropriate and safe for their specific circumstances.
Frequently asked questions
What conditions are associated with changes in the RAI1 gene?
Changes in the RAI1 gene are associated with several neurodevelopmental disorders. These include Smith-Magenis syndrome, which typically results from a loss of RAI1 function, and Potocki-Lupski syndrome and Yuan-Harel-Lupski syndrome, which are linked to having extra copies of the RAI1 gene.
How is the RAI1 gene involved in Smith-Magenis syndrome?
Research indicates that a partial or total loss of function of the RAI1 gene is responsible for most of the signs and symptoms of Smith-Magenis syndrome. This condition is characterised by intellectual disabilities, developmental delays, distinctive facial features, and sleep disturbances.
Is the RAI1 gene involved in circadian rhythms?
Yes, studies suggest that the RAI1 protein may help regulate the expression of genes that are involved in daily (circadian) rhythms, such as the sleep-wake cycle.
Where is the RAI1 gene located?
The RAI1 gene is located on chromosome 17, specifically at position 17p11.2. This location is within the short arm of chromosome 17.
References
- Mullegama SV, Alaimo JT, Fountain MD. RAI1 Overexpression Promotes Altered Circadian Gene Expression and Dyssomnia in Potocki-Lupski Syndrome. Journal of pediatric genetics. 2017. PMID: 28794907
- Huang WH, Guenthner CJ, Xu J. Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Neuron. 2016. PMID: 27693255
- Yuan B, Harel T, Gu S. Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome. American journal of human genetics. 2015. PMID: 26544804
- Williams SR, Zies D, Mullegama SV. Smith-Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity. American journal of human genetics. 2012. PMID: 22578325
- Carmona-Mora P, Encina CA, Canales CP. Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome. BMC molecular biology. 2010. PMID: 20738874
- Potocki L, Bi W, Treadwell-Deering D. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. American journal of human genetics. 2007. PMID: 17357070
- Girirajan S, Vlangos CN, Szomju BB. Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genetics in medicine : official journal of the American College of Medical Genetics. 2006. PMID: 16845274
- Bi W, Saifi GM, Girirajan S. RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome. American journal of medical genetics. Part A. 2006. PMID: 17041942
- Girirajan S, Elsas LJ 2nd, Devriendt K. RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. Journal of medical genetics. 2005. PMID: 15788730
- Bi W, Saifi GM, Shaw CJ. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Human genetics. 2004. PMID: 15565467
- Slager RE, Newton TL, Vlangos CN. Mutations in RAI1 associated with Smith-Magenis syndrome. Nature genetics. 2003. PMID: 12652298
- Potocki L, Chen KS, Park SS. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nature genetics. 2000. PMID: 10615134
- Adam MP, Bick S, Mirzaa GM. Smith-Magenis Syndrome. 1993. PMID: 20301487
- Adam MP, Bick S, Mirzaa GM. Potocki-Lupski Syndrome. 1993. PMID: 28837307