Alternative titles; symbols
HGNC Approved Gene Symbol: RAI1
SNOMEDCT: 401315004; ICD10CM: Q93.88;
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38) : 17:17,681,458-17,811,453 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p11.2 | Smith-Magenis syndrome | 182290 | Autosomal dominant; Isolated cases | 3 |
Seranski et al. (1999) identified RAI1 within an unstable region of chromosome 17p11.2 that is associated with several neurologic disorders and malignant diseases. RT-PCR detected expression in all adult and fetal tissues examined.
By cDNA selection, RT-PCR, and RACE using a fetal brain cDNA library, Seranski et al. (2001) obtained a full-length RAI1 cDNA. The deduced 1,863-amino acid protein contains an N-terminal polyglutamine stretch that is encoded by a polymorphic CAG repeat. The C terminus contains a polyserine stretch and 3 RAI1 domains, which share similarity with transcription factor-20 (TCF20; 603107). RAI1 has no potential membrane-spanning hydrophobic domains. Northern blot analysis revealed expression of several transcripts. An 8-kb transcript was expressed in all adult and fetal tissues and brain regions examined, except fetal liver. A 10-kb transcript was expressed weakly in heart, kidney, pancreas, stomach, thyroid, spinal cord, and lymph node. A 1.5-kb transcript was detected only in placenta.
By database analysis, Toulouse et al. (2003) determined that the CAG repeat was contained within the coding region of RAI1. By assembling ESTs and PCR of neuroblastoma cell line cDNA, cloned RAI1. The deduced protein contains 1,906 amino acids and shares 79% identity with mouse Rai1. Toulouse et al. (2003) noted that the polyglutamine tract encoded by the CAG repeat contains up to 18 glutamines in RAI1, and only 4 in the mouse homolog. Northern blot analysis confirmed expression of a single 8-kb transcript in all human tissues examined. Heart and brain showed highest expression. Northern blot analysis of individual brain regions detected similar expression in all regions analyzed except corpus callosum, where no expression was observed.
Seranski et al. (2001) determined that the RAI1 gene contains 8 exons and spans about 20 kb.
Toulouse et al. (2003) presented evidence that the RAI1 gene contains only 6 exons. In their model, the 5-prime untranslated region is encoded by 3 exons, and a significant CpG stretch is just upstream of exons 1 and 2. The promoter region contains binding sites for several regulatory proteins, including a retinoic acid-responsive element.
By genomic sequence analysis, Seranski et al. (1999) and Toulouse et al. (2003) mapped the RAI1 gene to chromosome 17p11.2, within the Smith-Magenis syndrome (SMS; 182290) critical region.
Walz et al. (2004) stated that the mouse Rai1 gene maps to a region of chromosome 11 that is syntenic with human chromosome 17p11.2.
Using quantitative real-time PCR, Williams et al. (2012) found that knockdown of RAI1 via small interfering RNA in HEK293T cells reduced expression of CLOCK (601851), a transcription factor that heterodimerizes with BMAL1 (ARNTL; 602550) to activate genes of the circadian feedback loop. Several CLOCK target genes and other components of the circadian feedback loop also showed dysregulation following knockdown of RAI1. Knockdown of RAI1 in U2OS-B cells reduced the circadian period length, as measured by BMAL1 expression. Human fibroblasts carrying a common SMS deletion, an atypical SMS deletion, or an RAI1 missense mutation (Q1562R; 607642.0005) exhibited dysregulated expression of core circadian genes. Chromatin immunoprecipitation, microarray analysis, and reporter gene assays revealed a functional RAI1-binding element in intron 1 of the CLOCK gene. Williams et al. (2012) concluded that RAI1 is a major positive regulator of CLOCK gene expression and is a circadian regulator.
Smith-Magenis Syndrome
By FISH, Seranski et al. (1999) determined that the RAI1 gene is deleted in SMS. Seranski et al. (2001) confirmed heterozygous deletion of the RAI1 gene in all SMS patients analyzed. The CAG repeats of 13 SMS patients were sequenced, but no expansions, frameshifts, or point mutations were detected. In normal individuals and SMS patients, 5 different RAI1 alleles were detected by gel electrophoresis, and sequence analysis showed that the CAG repeats ranged in size from 36 to 42 bp.
Smith-Magenis syndrome (SMS) is a mental retardation syndrome usually associated with deletions involving 17p11.2. Affected persons have characteristic behavioral abnormalities, including self-injurious behaviors and sleep disturbance, and distinct craniofacial and skeletal anomalies. Slager et al. (2003) identified dominant frameshift mutations (607642.0001-607642.0003) leading to premature termination of the RAI1 protein in 3 individuals who had phenotypic features consistent with SMS but did not have 17p11.2 deletions detectable by standard fluorescence in situ hybridization techniques. They suggested that SMS may be similar to previously described microdeletion syndromes in which a single gene is implicated in most of the features but other deleted genes may modify the overall phenotype. Haploinsufficiency of RAI1 is probably responsible for the behavioral, neurologic, otolaryngologic, and craniofacial features of the syndrome, but more variable features such as heart and renal defects are probably due to hemizygosity of other genes in the 17p11.2 region.
Bi et al. (2004) reported 2 novel RAI1 mutations, 1 frameshift and 1 nonsense mutation, in 2 SMS patients without FISH-detectable deletions. Comparisons of the clinical features of these 2 patients, 3 of the previously reported RAI1 point mutation cases, and the patients with a common deletion suggested that most of the clinical features in SMS result from RAI1 mutation, although phenotypic variability exists even among individuals with RAI1 point mutations. Bioinformatics analyses of RAI1 and comparative genomics between human and mouse orthologs revealed a zinc finger-like plant homeodomain (PHD) at the C terminus that is conserved in the trithorax group of chromatin-based transcription regulators. These findings suggested that RAI1 is involved in transcriptional control through a multiprotein complex whose function may be altered in individuals with SMS.
Girirajan et al. (2005) performed mutation analysis of the RAI1 gene in 4 individuals with features consistent with SMS and without 17p11.2 deletions. Two patients were found to have small deletions in RAI1 resulting in frameshift and premature termination of the protein (607642.0006 and 607642.0007, respectively). Missense mutations (607642.0004 and 607642.0005, respectively) were identified in the other 2 patients. Orthologs across other genomes showed that these missense mutations occurred in identically conserved regions of the gene. The mutations were de novo. The patients' clinical features differed from those found in 17p11.2 deletions by general absence of short stature and lack of visceral anomalies. All 4 patients had developmental delay, reduced motor and cognitive skills, craniofacial and behavioral anomalies, and sleep disturbance. Seizures, not previously thought to be associated with RAI1 mutations, were observed in 1 patient. Thus, haploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioral, and neurologic signs and symptoms.
Bi et al. (2006) described 2 patients with SMS and point mutations in the RAI1 gene. One was a 9-year-old boy who had a de novo 1-bp deletion within a heptameric C-tract; the authors noted that of the 11 mutations reported in patients with SMS, the 5 frameshifts due to single basepair insertions or deletions all occurred within polyC tracts, and 2 were within the same heptameric C-tract. The other patient was a 5-year-old girl who was a compound heterozygote for a missense mutation inherited from her unaffected father and an 18-copy CAG repeat inherited from her mother, who had a history of ADHD. Her sister, who was obese and had emotional problems, carried the missense mutation but not the large CAG repeat; the missense mutation was not found in 120 ethnically matched controls. Bi et al. (2006) suggested that the apparent SMS phenotype observed in the female patient might result from the combination of the rare nucleotide change and the relatively large CAG repeat.
Girirajan et al. (2006) reported the molecular and genotype-phenotype analyses of 31 patients with SMS who carry 17p11.2 deletions or intergenic mutations, respectively, and were compared for 30 characteristic features of the disorder by the Fisher exact test. Eight of the 31 individuals carried a common 3.5-Mb deletion, whereas 10 of 31 individuals carried smaller deletions, 2 individuals carried larger deletions, and 1 individual carried an atypical 17p11.2 deletion. Ten patients with nondeletion harbored a heterozygous mutation in RAI1. Phenotype comparison between patients with deletions and patients with RAI1 mutations showed that 21 of 30 SMS features are the result of haploinsufficiency of RAI1, whereas cardiac anomalies, speech and motor delay, hypotonia, short stature, and hearing loss are associated with 17p11.2 deletions rather than RAI1 mutations (P less than 0.05). Further, patients with smaller deletions show features similar to those with RAI1 mutations. Girirajan et al. (2006) concluded that although RAI1 is the primary gene responsible for most features of SMS, other genes within 17p11.2 contribute to the variable features and overall severity of the syndrome.
Spinocerebellar Ataxia 2
Spinocerebellar ataxia type 2 (SCA2; 183090) is an autosomal dominant disorder caused by the expansion of a polymorphic (CAG)n tract, which is translated into an expanded polyglutamine tract in the ataxin-2 protein (ATX2; 601517). Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remained unexplained. Part of the remaining variance in polyglutamine disorders may be due to other familial factors. The ability of polyglutamine tracts to interact with each other, as well as the presence of intranuclear inclusions in other polyglutamine disorders, led Hayes et al. (2000) to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, they used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. They found that the RAI1 locus contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the SCA2 expanded repeat. No such effect was observed in the case of SCA3 (109150). The result implicated RAI1 as a possible contributor to SCA2 neurodegeneration and raised the possibility that other CAG-containing proteins may play a role in the pathogenesis of various polyglutamine disorders.
Joober et al. (1999) identified a CAG repeat polymorphism that was associated with the severity of schizophrenia (181500) and patient response to neuroleptic medication. They found that schizophrenic patients who were able to respond to neuroleptic medication displayed a significantly shorter CAG repeat compared to controls. Nonresponders did not differ from controls.
Using retrovirus-mediated chromosome engineering to create nested deletions of the mouse homolog to the SMS critical region, Yan et al. (2004) constructed 3 lines of mice with 590- or 595-kb deletions, Df(11)17-1, Df(11)17-2, and Df(11)17-3. Both craniofacial abnormalities and obesity were observed, but the penetrance of the craniofacial phenotype was markedly reduced when compared with Df(11)17 mice, which have a 2-Mb deletion. The authors proposed that the loss of Rai1 may be responsible for the craniofacial abnormalities and obesity.
Bi et al. (2005) generated a null RAI1 allele in mice. Obesity and craniofacial abnormalities were observed in Rai1 +/- mice, but the penetrance of craniofacial anomalies was further reduced in Rai1 +/- mice compared with Df(11)17-1 or Df(11)17 mice. Most Rai1 -/- mice died during gastrulation and organogenesis, and survivors were growth retarded and displayed malformations in both the craniofacial and the axial skeleton. Using Rai1-fusion constructs, the authors showed that Rai1 is translocated to the nucleus and has transactivation activity. Bi et al. (2005) concluded that Rai1 functions as a transcriptional regulator and may be important for embryonic and postnatal development.
Walz et al. (2004) found that heterozygous Df(11)17 mice displayed an average circadian period that was significantly shorter than that of wildtype littermates.
Mice with a heterozygous duplication, Dp(11)17, of the region on mouse chromosome 11 that is syntenic to human chromosome 17 are underweight and show behavioral anomalies such as impaired contextual fear conditioning (Walz et al. (2003, 2004)). Walz et al. (2006) generated compound heterozygous mice with a Dp(11)17 allele and a null Rai1 allele, thus resulting in normal disomic gene dosage of Rai1. Normal Rai1 dosage rescued many of the phenotypes observed in heterozygous Dp(11)17 mice, who have 3 copies of the gene, including normalization of body weight and partial normalization of behavior. The phenotype was rescued despite altered trisomic copy number of the other 18 or so genes in the region. Walz et al. (2006) concluded that duplication of Rai1 is responsible for decreased body weight in Dp(11)17 mice and that Rai1 is a dosage-sensitive gene involved in body weight control and complex behavioral responses.
Girirajan et al. (2008) generated transgenic mice with 4 and 6 copies of the Rai1 gene. The mice showed growth retardation, increased locomotor activity, impaired sensorimotor activity, and abnormal anxiety-related behavior compared to wildtype littermates. Rai1-transgenic mice had an altered gait, decreased forelimb grip strength, and a dominant social behavior. There was a dose-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurologic deficits, and increased hyperactivity in mice with higher Rai1 expression. Girirajan et al. (2008) concluded that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurologic and behavioral functions, providing evidence for several dosage-thresholds for phenotypic manifestations in humans.
Burns et al. (2010) investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1. Rai1 +/- mice were hyperphagic, had an impaired satiety response, and had an altered abdominal and subcutaneous fat distribution, with Rai1 +/- female mice having a higher proportion of abdominal fat when compared with wildtype female mice. Brain-derived neurotrophic factor (BDNF; 113505), a gene associated with hyperphagia and obesity, was downregulated in the Rai1 +/- mouse hypothalamus, and reporter studies showed that RAI1 directly regulated the expression of BDNF.
Using quantitative real-time PCR, Williams et al. (2012) found that Rai1 +/- mouse hypothalamus showed dysregulated expression of Clock and other circadian genes during light and dark phases.
In a person with Smith-Magenis syndrome (182290), Slager et al. (2003) identified deletion on 1 RAI1 allele of a single cytosine in a run of 6 cytosines. The 4929delC on the coding strand produced a frameshift, introducing 74 incorrect amino acids and truncating protein.
In a person with Smith-Magenis syndrome (182290), Slager et al. (2003) observed deletion of 1 C from a run of 4 Cs ending at nucleotide position 1308 in exon 3 of RAI1. This deletion caused a frameshift that incorporated 34 incorrect amino acids beginning at amino acid position 437, followed by a stop codon and premature termination of the protein.
In a person with Smith-Magenis syndrome (182290), Slager et al. (2003) found a deletion of 29 basepairs in exon 3 of the RAI gene on 1 allele. This deletion produced a frameshift that introduced 8 incorrect amino acids followed by a stop codon, truncating the protein.
In a 17-year-old adopted boy of northern European and Jewish ancestry with features considered consistent with SMS (182290), Girirajan et al. (2005) detected a heterozygous 5423G-A mutation in the RAI1 gene underlying a serine-to-asparagine change at amino acid 1808 (S1808N).
In an 11-year-old white girl with mental retardation, progressive speech delay, stereotypic behavior, intractable complex seizures, and facial dysmorphism consistent with a diagnosis of Smith-Magenis syndrome (182290), Girirajan et al. (2005) described a missense mutation in the RAI1 protein, gln1562 to arg (Q1562R), resulting from a heterozygous adenine-to-guanine transition at nucleotide 4685.
Using quantitative real-time PCR, Williams et al. (2012) showed that fibroblasts carrying the Q1562R mutation showed dysregulated expression of genes required for circadian rhythmicity.
In a 14-year-old boy of European descent with features considered consistent with SMS (182290), Girirajan et al. (2005) found a 1-bp deletion in the RAI1 gene, 3801delC, in heterozygous state. The deletion resulted in a frameshift starting at amino acid 1267, leading to misincorporation of 46 amino acids and a downstream stop codon.
Girirajan et al. (2005) found that a 19-year-old woman of European descent with features consistent with SMS (182290) had a 19-bp deletion in the RAI1 gene (253del19).
Bi, W., Ohyama, T., Nakamura, H., Yan, J., Visvanathan, J., Justice, M. J., Lupski, J. R. Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. Hum. Molec. Genet. 14: 983-995, 2005. [PubMed: 15746153] [Full Text: https://doi.org/10.1093/hmg/ddi085]
Bi, W., Saifi, G. M., Girirajan, S., Shi, X., Szomju, B., Firth, H., Magenis, R. E., Potocki, L., Elsea, S. H., Lupski, J. R. RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome. Am. J. Med. Genet. 140A: 2454-2463, 2006. [PubMed: 17041942] [Full Text: https://doi.org/10.1002/ajmg.a.31510]
Bi, W., Saifi, G. M., Shaw, C. J., Walz, K., Fonseca, P., Wilson, M., Potocki, L., Lupski, J. R. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum. Genet. 115: 515-524, 2004. [PubMed: 15565467] [Full Text: https://doi.org/10.1007/s00439-004-1187-6]
Burns, B., Schmidt, K., Williams, S. R., Kim, S., Girirajan, S., Elsea, S. H. Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. Hum. Molec. Genet. 19: 4026-4042, 2010. [PubMed: 20663924] [Full Text: https://doi.org/10.1093/hmg/ddq317]
Girirajan, S., Elsas, L. J., II, Devriendt, K., Elsea, S. H. RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J. Med. Genet. 42: 820-828, 2005. [PubMed: 15788730] [Full Text: https://doi.org/10.1136/jmg.2005.031211]
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Joober, R., Benkelfat, C., Toulouse, A., Lafreniere, R. G. A., Lal, S., Ajroud, S., Turecki, G., Bloom, D., Labelle, A., Lalonde, P., Alda, M., Morgan, K., Palmour, R., Rouleau, G. A. Analysis of 14 CAG repeat-containing genes in schizophrenia. Am. J. Med. Genet. 88: 694-699, 1999. [PubMed: 10581491]
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Seranski, P., Hoff, C., Radelof, U., Hennig, S., Reinhardt, R., Schwartz, C. E., Heiss, N. S., Poustka, A. RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 270: 69-76, 2001. [PubMed: 11404004] [Full Text: https://doi.org/10.1016/s0378-1119(01)00415-2]
Slager, R. E., Newton, T. L., Vlangos, C. N., Finucane, B., Elsea, S. H. Mutations in RAI1 associated with Smith-Magenis syndrome. Nature Genet. 33: 466-468, 2003. [PubMed: 12652298] [Full Text: https://doi.org/10.1038/ng1126]
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Walz, K., Caratini-Rivera, S., Bi, W., Fonseca, P., Mansouri, D. L., Lynch, J., Vogel, H., Noebels, J. L., Bradley, A., Lupski, J. R. Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. Molec. Cell. Biol. 23: 3646-3655, 2003. [PubMed: 12724422] [Full Text: https://doi.org/10.1128/MCB.23.10.3646-3655.2003]
Walz, K., Paylor, R., Yan, J., Bi, W., Lupski, J. R. Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). J. Clin. Invest. 116: 3035-3041, 2006. [PubMed: 17024248] [Full Text: https://doi.org/10.1172/JCI28953]
Walz, K., Spencer, C., Kaasik, K., Lee, C. C., Lupski, J. R., Paylor, R. Behavioral characterization of mouse models for Smith-Magenis syndrome and dup(17)(p11.2p11.2). Hum. Molec. Genet. 13: 367-378, 2004. [PubMed: 14709593] [Full Text: https://doi.org/10.1093/hmg/ddh044]
Williams, S. R., Zies, D., Mullegama, S. V., Grotewiel, M. S., Elsea, S. H. 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. 90: 941-949, 2012. [PubMed: 22578325] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.013]
Yan, J., Keener, V. W., Bi, W., Walz, K., Bradley, A., Justice, M. J., Lupski, J. R. Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome. Hum. Molec. Genet. 13: 2613-2624, 2004. [PubMed: 15459175] [Full Text: https://doi.org/10.1093/hmg/ddh288]