Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE81207 | GEO | 2017/01/03
SECONDARY ACCESSION(S): PRJNA320885
REPOSITORIES: GEO
Similar Datasets
Project description:Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome
| PRJNA320885 | ENA
Project description:Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1+ or SF1+ cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder.
| S-EPMC5098476 | biostudies-literature
Project description:Smith-Magenis syndrome (SMS; OMIM #182290) is a complex genetic disorder characterized by distinctive physical features, developmental delay, cognitive impairment, and a typical behavioral phenotype. SMS is caused by interstitial 17p11.2 deletions, encompassing multiple genes and including the retinoic acid-induced 1 gene (RAI1), or by mutations in RAI1 itself. About 10% of all the SMS patients, in fact, carry an RAI1 mutation responsible for the phenotype. RAI1 (OMIM *607642) is a dosage-sensitive gene expressed in many tissues and highly conserved among species. Over the years, several studies have demonstrated that RAI1 (or its homologs in animal models) acts as a transcriptional factor implicated in embryonic neurodevelopment, neuronal differentiation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucose metabolisms, behavioral functions, and circadian activity. Patients with RAI1 pathogenic variants show some phenotypic differences when compared to those carrying the typical deletion. They usually have lower incidence of hypotonia and less cognitive impairment than those with 17p11.2 deletions but more frequently show the behavioral characteristics of the syndrome and overeating issues. These differences reflect the primary pathogenetic role of RAI1 without the pathogenetic contribution of the other genes included in the typical 17p11.2 deletion. The better comprehension of physiological roles of RAI1, its molecular co-workers and interactors, and its contribution in determining the typical SMS phenotype will certainly open a new path for therapeutic interventions.
| S-EPMC5680963 | biostudies-literature
Project description:BackgroundSmith-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.ObjectiveAnalysis 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.ResultsTwo 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.ConclusionsHaploinsufficiency of the RAI1 gene is associated with most features of SMS, including craniofacial, behavioural, and neurological signs and symptoms.
| S-EPMC1735950 | biostudies-literature
Project description:Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation.
| S-EPMC3445574 | biostudies-literature
Project description:Smith-Magenis syndrome (SMS; OMIM 182290) is a genomic disorder characterized by multiple congenital anomalies, intellectual disability, behavioral abnormalities, and disordered sleep resulting from an ~3.7 Mb deletion copy number variant (CNV) on chromosome 17p11.2 or from point mutations in the gene RAI1. The reciprocal duplication of this region results in another genomic disorder, Potocki-Lupski syndrome (PTLS; OMIM 610883), characterized by autism, intellectual disability, and congenital anomalies. We previously used chromosome-engineering and gene targeting to generate mouse models for PTLS (Dp(11)17/+), and SMS due to either deletion CNV or gene knock-out (Df(11)17-2/+ and Rai1(+/-) , respectively) and we observed phenotypes in these mouse models consistent with their associated human syndromes. To investigate the contribution of individual genes to the circadian phenotypes observed in SMS, we now report the analysis of free-running period lengths in Rai1(+/-) and Df(11)17-2/+ mice, as well as in mice deficient for another known circadian gene mapping within the commonly deleted/duplicated region, Dexras1, and we compare these results to those previously observed in Dp(11)17/+ mice. Reduced free-running period lengths were seen in Df(11)17-2/+, Rai1(+/-) , and Dexras1(-/-) , but not Dexras1(+/-) mice, suggesting that Rai1 may be the primary gene underlying the circadian defects in SMS. However, we cannot rule out the possibility that cis effects between multiple haploinsufficient genes in the SMS critical interval (e.g., RAI1 and DEXRAS1) either exacerbate the circadian phenotypes observed in SMS patients with deletions or increase their penetrance in certain environments. This study also confirms a previous report of abnormal circadian function in Dexras1(-/-) mice.
| S-EPMC4086898 | biostudies-literature
Project description:Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions.
| S-EPMC3977224 | biostudies-literature
Project description:Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ?3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.
| S-EPMC3152558 | biostudies-literature
Project description:Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3-4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7-8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.
| S-EPMC6196530 | biostudies-other
Project description:Smith-Magenis Syndrome is a contiguous gene syndrome in which the dosage sensitive gene has been identified: the Retinoic Acid Induced 1 (RAI1). Little is known about the function of human RAI1.We generated the full-length cDNA of the wild type protein and five mutated forms: RAI1-HA 2687delC, RAI1-HA 3103delC, RAI1 R960X, RAI1-HA Q1562R, and RAI1-HA S1808N. Four of them have been previously associated with SMS clinical phenotype. Molecular weight, subcellular localization and transcription factor activity of the wild type and mutant forms were studied by western blot, immunofluorescence and luciferase assays respectively. The wild type protein and the two missense mutations presented a higher molecular weight than expected, localized to the nucleus and activated transcription of a reporter gene. The frameshift mutations generated a truncated polypeptide with transcription factor activity but abnormal subcellular localization, and the same was true for the 1-960aa N-terminal half of RAI1. Two different C-terminal halves of the RAI1 protein (1038aa-end and 1229aa-end) were able to localize into the nucleus but had no transactivation activity.Our results indicate that transcription factor activity and subcellular localization signals reside in two separate domains of the protein and both are essential for the correct functionality of RAI1. The pathogenic outcome of some of the mutated forms can be explained by the dissociation of these two domains.
| S-EPMC2939504 | biostudies-literature