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J Med Genet. 2005 November; 42(11): 820–828.
Published online 2005 March 23. doi:  10.1136/jmg.2005.031211
PMCID: PMC1735950

RAI1 variations in Smith–Magenis syndrome patients without 17p11.2 deletions


Background: Smith–Magenis syndrome (SMS) (OMIM No 182290) is a mental retardation syndrome characterised by behavioural abnormalities, including self injurious behaviours, sleep disturbance, and distinct craniofacial and skeletal anomalies. It is usually associated with deletion involving 17p11.2 and is estimated to occur in 1/25 000 births. Heterozygous frameshift mutations leading to protein truncation in retinoic acid induced 1 gene (RAI1) have been identified in individuals with phenotypic features consistent with SMS. RAI1 lies within the 17p11.2 locus, but these patients did not have 17p11.2 deletions.

Objective: Analysis of four individuals with features consistent with SMS for variations in RAI1, using a polymerase chain reaction and sequencing strategy. None of these patients carry 17p11.2 deletions.

Results: Two patients had small deletions in RAI1 resulting in frameshift and premature truncation of the protein. Missense mutations were identified in the other two. Orthologs across other genomes showed that these missense mutations occurred in identically conserved regions of the gene. The mutations were de novo, as all parental samples were normal. Several polymorphisms were also observed, including new and reported SNPs. The patients' clinical features differed from those found in 17p11.2 deletion by general absence of short stature and lack of visceral anomalies. All four patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioural anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 mutations, were observed in one patient of the cohort.

Conclusions: Haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioural, and neurological signs and symptoms.

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Selected References

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  • Smith AC, McGavran L, Robinson J, Waldstein G, Macfarlane J, Zonona J, Reiss J, Lahr M, Allen L, Magenis E. Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet. 1986 Jul;24(3):393–414. [PubMed]
  • Allanson JE, Greenberg F, Smith AC. The face of Smith-Magenis syndrome: a subjective and objective study. J Med Genet. 1999 May;36(5):394–397. [PMC free article] [PubMed]
  • Liburd N, Ghosh M, Riazuddin S, Naz S, Khan S, Ahmed Z, Riazuddin S, Liang Y, Menon PS, Smith T, et al. Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum Genet. 2001 Nov;109(5):535–541. [PubMed]
  • Smith AC, Dykens E, Greenberg F. Behavioral phenotype of Smith-Magenis syndrome (del 17p11.2). Am J Med Genet. 1998 Mar 28;81(2):179–185. [PubMed]
  • Potocki L, Glaze D, Tan DX, Park SS, Kashork CD, Shaffer LG, Reiter RJ, Lupski JR. Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. J Med Genet. 2000 Jun;37(6):428–433. [PMC free article] [PubMed]
  • De Leersnyder H, De Blois MC, Claustrat B, Romana S, Albrecht U, Von Kleist-Retzow JC, Delobel B, Viot G, Lyonnet S, Vekemans M, et al. Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr. 2001 Jul;139(1):111–116. [PubMed]
  • Dykens EM, Smith AC. Distinctiveness and correlates of maladaptive behaviour in children and adolescents with Smith-Magenis syndrome. J Intellect Disabil Res. 1998 Dec;42(Pt 6):481–489. [PubMed]
  • Smith Ann C M, Gropman Andrea L, Bailey-Wilson Joan E, Goker-Alpan Ozlem, Elsea Sarah H, Blancato Jan, Lupski James R, Potocki Lorraine. Hypercholesterolemia in children with Smith-Magenis syndrome: del (17) (p11.2p11.2). Genet Med. 2002 May-Jun;4(3):118–125. [PubMed]
  • Greenberg F, Guzzetta V, Montes de Oca-Luna R, Magenis RE, Smith AC, Richter SF, Kondo I, Dobyns WB, Patel PI, Lupski JR. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet. 1991 Dec;49(6):1207–1218. [PubMed]
  • Trask BJ, Mefford H, van den Engh G, Massa HF, Juyal RC, Potocki L, Finucane B, Abuelo DN, Witt DR, Magenis E, et al. Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients. Hum Genet. 1996 Dec;98(6):710–718. [PubMed]
  • Chen KS, Manian P, Koeuth T, Potocki L, Zhao Q, Chinault AC, Lee CC, Lupski JR. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet. 1997 Oct;17(2):154–163. [PubMed]
  • Vlangos Christopher N, Wilson Meredith, Blancato Jan, Smith Ann C M, Elsea Sarah H. Diagnostic FISH probes for del(17)(p11.2p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene. Am J Med Genet A. 2005 Jan 30;132A(3):278–282. [PubMed]
  • Slager Rebecca E, Newton Tiffany Lynn, Vlangos Christopher N, Finucane Brenda, Elsea Sarah H. Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet. 2003 Apr;33(4):466–468. [PubMed]
  • Toulouse André, Rochefort Daniel, Roussel Julie, Joober Ridha, Rouleau Guy A. Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia. Genomics. 2003 Aug;82(2):162–171. [PubMed]
  • Imai Y, Suzuki Y, Matsui T, Tohyama M, Wanaka A, Takagi T. Cloning of a retinoic acid-induced gene, GT1, in the embryonal carcinoma cell line P19: neuron-specific expression in the mouse brain. Brain Res Mol Brain Res. 1995 Jul;31(1-2):1–9. [PubMed]
  • Bi Weimin, Saifi G Mustafa, Shaw Christine J, Walz Katherina, Fonseca Patricia, Wilson Meredith, Potocki Lorraine, Lupski James R. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet. 2004 Nov;115(6):515–524. [PubMed]
  • Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J, Killian J, Murphy MA, Williamson D, Brown F, Dutton R, et al. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2) Am J Med Genet. 1996 Mar 29;62(3):247–254. [PubMed]
  • Finucane BM, Konar D, Haas-Givler B, Kurtz MB, Scott CI., Jr The spasmodic upper-body squeeze: a characteristic behavior in Smith-Magenis syndrome. Dev Med Child Neurol. 1994 Jan;36(1):78–83. [PubMed]
  • Finucane B, Dirrigl KH, Simon EW. Characterization of self-injurious behaviors in children and adults with Smith-Magenis syndrome. Am J Ment Retard. 2001 Jan;106(1):52–58. [PubMed]
  • Joober R, Benkelfat C, Toulouse A, Lafrenière RG, Lal S, Ajroud S, Turecki G, Bloom D, Labelle A, Lalonde P, et al. Analysis of 14 CAG repeat-containing genes in schizophrenia. Am J Med Genet. 1999 Dec 15;88(6):694–699. [PubMed]
  • Hayes S, Turecki G, Brisebois K, Lopes-Cendes I, Gaspar C, Riess O, Ranum LP, Pulst SM, Rouleau GA. CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2). Hum Mol Genet. 2000 Jul 22;9(12):1753–1758. [PubMed]
  • Seranski P, Hoff C, Radelof U, Hennig S, Reinhardt R, Schwartz CE, Heiss NS, Poustka A. RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene. 2001 May 30;270(1-2):69–76. [PubMed]
  • Maier D, Stumm G, Kuhn K, Preiss A. Hairless, a Drosophila gene involved in neural development, encodes a novel, serine rich protein. Mech Dev. 1992 Aug;38(2):143–156. [PubMed]
  • Onodera O, Oyake M, Takano H, Ikeuchi T, Igarashi S, Tsuji S. Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS. Am J Hum Genet. 1995 Nov;57(5):1050–1060. [PubMed]
  • Gerber HP, Seipel K, Georgiev O, Höfferer M, Hug M, Rusconi S, Schaffner W. Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science. 1994 Feb 11;263(5148):808–811. [PubMed]
  • Milne Thomas A, Briggs Scott D, Brock Hugh W, Martin Mary Ellen, Gibbs Denise, Allis C David, Hess Jay L. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002 Nov;10(5):1107–1117. [PubMed]
  • Nakamura Tatsuya, Mori Toshiki, Tada Shinichiro, Krajewski Wladyslaw, Rozovskaia Tanya, Wassell Richard, Dubois Garrett, Mazo Alexander, Croce Carlo M, Canaani Eli. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002 Nov;10(5):1119–1128. [PubMed]
  • Aasland R, Gibson TJ, Stewart AF. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem Sci. 1995 Feb;20(2):56–59. [PubMed]
  • Rekdal C, Sjøttem E, Johansen T. The nuclear factor SPBP contains different functional domains and stimulates the activity of various transcriptional activators. J Biol Chem. 2000 Dec 22;275(51):40288–40300. [PubMed]

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