The RAI1 gene provides instructions for making a protein that is active in cells throughout the body, particularly nerve cells (neurons) in the brain. Located in the nucleus of the cell, the RAI1 protein helps control the activity (expression) of certain genes. Most of the genes regulated by RAI1 have not been identified. However, studies suggest that this protein controls the expression of several genes involved in daily (circadian) rhythms, such as the sleep-wake cycle. The RAI1 protein also appears to play a role in development of the brain and of bones in the head and face (craniofacial bones).
Health Conditions Related to Genetic Changes
Having an extra copy of the RAI1 gene in each cell is thought to underlie many of the major features of Potocki-Lupski syndrome. This condition is characterized by delayed development, mild to moderate intellectual disability, behavioral problems including autism spectrum disorder (which affects social interaction and communication), sleep disturbances, and other health problems. The condition results from abnormal copying (duplication) of a small piece of the short (p) arm of chromosome 17 at position p11.2. In about two-thirds of affected individuals, the duplicated segment includes approximately 3.7 million DNA building blocks (base pairs), also written as 3.7 megabases (Mb). (A deletion of this segment causes Smith-Magenis syndrome, described below.) In the remaining one-third of cases, the duplication is larger or smaller, ranging from less than 1 Mb to almost 20 Mb. All of these duplications affect one of the two copies of chromosome 17 in each cell.
All of the duplications known to cause Potocki-Lupski syndrome contain the RAI1 gene. Studies suggest that the duplication increases the amount of RAI1 protein, which disrupts the expression of genes that influence circadian rhythms. These changes may account for the sleep disturbances that occur with Potocki-Lupski syndrome. Too much RAI1 protein may also disrupt brain development, which could account for delayed development, intellectual disability, behavioral problems, and other neurological features of this condition. Development of the bones in the head and face may also be affected, leading to subtle facial differences in people with Potocki-Lupski syndrome.More About This Health Condition
Researchers believe that a partial or total loss of function of the RAI1 gene accounts for most of the signs and symptoms of Smith-Magenis syndrome. The major features of this condition include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, behavioral problems, and other abnormalities affecting many parts of the body.
In most people with Smith-Magenis syndrome, the condition results from a deletion of a small piece of chromosome 17 in each cell. Most often, this chromosome segment, located at 17p11.2, is the same one that is duplicated in Potocki-Lupski syndrome (described above). Occasionally the deletion is larger or smaller. All of the deletions affect one of the two copies of chromosome 17 in each cell.
All of the deletions known to cause Smith-Magenis syndrome contain the RAI1 gene. Studies suggest that the deletion leads to a reduced amount of RAI1 protein in cells, which disrupts the expression of genes involved in circadian rhythms. These changes may account for the sleep disturbances that occur with Smith-Magenis syndrome. It is unclear how a loss of one copy of the RAI1 gene leads to the other physical, mental, and behavioral problems associated with this condition.
A small percentage of people with Smith-Magenis syndrome have a mutation in the RAI1 gene instead of a chromosomal deletion. Although these individuals have many of the major features of the condition, they are less likely than people with a deletion to have certain other features, including short stature, hearing loss, and heart or kidney abnormalities. It is likely that, in people with a deletion, the loss of other genes in the deleted region accounts for these additional signs and symptoms; the role of these genes is under study.More About This Health Condition
Having an extra copy of the RAI1 gene in each cell is thought to underlie many of the major features of Yuan-Harel-Lupski (YUHAL) syndrome, which is characterized by multiple neurological problems. This condition results from duplication of a small piece of chromosome 17 in a region designated p12-p11.2. In YUHAL syndrome, the duplicated segments can range in size from 3.2 Mb to 19.7 Mb. These duplications affect one of the two copies of chromosome 17 in each cell.
The duplications that cause YUHAL syndrome all contain the RAI1 gene and a nearby gene called PMP22; the segments may also contain additional genes. Some features of YUHAL syndrome, such as delayed development, behavioral and sleep problems, and unusual facial features, are similar to those of Potocki-Lupski syndrome (described above) and are likely caused by an extra copy of the RAI1 gene. Other features of YUHAL syndrome, such as muscle weakness and decreased sensitivity to touch, heat, and cold in the lower legs and feet, likely result from an extra copy of the PMP22 gene.More About This Health Condition
Other Names for This Gene
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Bi W, Saifi GM, Girirajan S, Shi X, Szomju B, Firth H, Magenis RE, Potocki L, Elsea SH, Lupski JR. RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome. Am J Med Genet A. 2006 Nov 15;140(22):2454-63. doi: 10.1002/ajmg.a.31510. Citation on PubMed
- Bi W, Saifi GM, Shaw CJ, Walz K, Fonseca P, Wilson M, Potocki L, Lupski JR. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet. 2004 Nov;115(6):515-24. doi: 10.1007/s00439-004-1187-6. Epub 2004 Sep 30. Citation on PubMed
- Carmona-Mora P, Encina CA, Canales CP, Cao L, Molina J, Kairath P, Young JI, Walz K. Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome. BMC Mol Biol. 2010 Aug 25;11:63. doi: 10.1186/1471-2199-11-63. Citation on PubMed or Free article on PubMed Central
- Girirajan S, Elsas LJ 2nd, Devriendt K, Elsea SH. RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J Med Genet. 2005 Nov;42(11):820-8. doi: 10.1136/jmg.2005.031211. Epub 2005 Mar 23. Citation on PubMed or Free article on PubMed Central
- Girirajan S, Vlangos CN, Szomju BB, Edelman E, Trevors CD, Dupuis L, Nezarati M, Bunyan DJ, Elsea SH. Genotype-phenotype correlation in Smith-Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genet Med. 2006 Jul;8(7):417-27. doi: 10.1097/01.gim.0000228215.32110.89. Citation on PubMed
- Huang WH, Guenthner CJ, Xu J, Nguyen T, Schwarz LA, Wilkinson AW, Gozani O, Chang HY, Shamloo M, Luo L. Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Neuron. 2016 Oct 19;92(2):392-406. doi: 10.1016/j.neuron.2016.09.019. Epub 2016 Sep 29. Citation on PubMed or Free article on PubMed Central
- Mullegama SV, Alaimo JT, Fountain MD, Burns B, Balog AH, Chen L, Elsea SH. RAI1 Overexpression Promotes Altered Circadian Gene Expression and Dyssomnia in Potocki-Lupski Syndrome. J Pediatr Genet. 2017 Sep;6(3):155-164. doi: 10.1055/s-0037-1599147. Epub 2017 Mar 7. Citation on PubMed or Free article on PubMed Central
- Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski JR. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet. 2007 Apr;80(4):633-49. doi: 10.1086/512864. Epub 2007 Feb 26. Citation on PubMed or Free article on PubMed Central
- Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA, Kimonis V, Summers AM, Meschino WS, Anyane-Yeboa K, Kashork CD, Shaffer LG, Lupski JR. Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet. 2000 Jan;24(1):84-7. doi: 10.1038/71743. Citation on PubMed
- Potocki L, Neira-Fresneda J, Yuan B. Potocki-Lupski Syndrome. 2017 Aug 24. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK447920/ Citation on PubMed
- Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH. Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet. 2003 Apr;33(4):466-8. doi: 10.1038/ng1126. Epub 2003 Mar 24. Citation on PubMed
- Smith ACM, Boyd KE, Brennan C, Charles J, Elsea SH, Finucane BM, Foster R, Gropman A, Girirajan S, Haas-Givler B. Smith-Magenis Syndrome. 2001 Oct 22 [updated 2022 Mar 10]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1310/ Citation on PubMed
- Williams SR, Zies D, Mullegama SV, Grotewiel MS, Elsea SH. Smith-Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity. Am J Hum Genet. 2012 Jun 8;90(6):941-9. doi: 10.1016/j.ajhg.2012.04.013. Epub 2012 May 10. Citation on PubMed or Free article on PubMed Central
- Yuan B, Harel T, Gu S, Liu P, Burglen L, Chantot-Bastaraud S, Gelowani V, Beck CR, Carvalho CM, Cheung SW, Coe A, Malan V, Munnich A, Magoulas PL, Potocki L, Lupski JR. Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome. Am J Hum Genet. 2015 Nov 5;97(5):691-707. doi: 10.1016/j.ajhg.2015.10.003. Citation on PubMed or Free article on PubMed Central
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