Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome

Carmona-Mora, Paulina; Encina, Carolina; Canales, Cesar P; Cao, Lei; Molina, Jéssica; Kairath, Pamela; Young, Juan I.; Walz, Katherina

doi:10.1186/1471-2199-11-63

Cited by 36 publications

(65 citation statements)

References 45 publications

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“…15 As shown in Figure 3c, both RAI1-HA R1217Q and RAI1-HA Q1389R variant proteins showed an increment of 105.2±8.4 and 93.85±10.1 percentage of activation of luciferase activity respectively, when compared with the wild type as 100% (no significant changes for any variant). These data indicate that the variant polypeptides retained the transcription factor capacity.…”

Section: Rai1 Alterations In Patients With Features Suggestive Of Smimentioning

confidence: 93%

“…15 The transcription factor activity of RAI1 has been linked to its N-terminal half and the C-terminal half directs it to the nucleus. 15 However, all SMS-associated missense mutations analyzed till date did not produce proteins that differed from the wild-type RAI1 protein either in their subcellular localization or in their transcription factor activity function, 15,16 suggesting that there are other essential RAI1 functions related with the SMS clinical phenotype. A functional network module for SMS has been suggested based on a genome-wide gene expression study using RAI1 haploinsufficient HEK293T cells.…”

Section: Smith-magenis Syndrome (Sms Mim 182290mentioning

confidence: 99%

“…All transfections were performed according to the manufacturer's protocols described previously. 15 For immunofluorescence, cells were fixed 24 h after transfection with 4% paraformaldehyde followed by permeabilization with 0.2% Triton X-100 in phosphate-buffered saline. Subcellular localization of RAI1-HA wild-type and mutant forms were detected using the anti-HA high-affinity antibody (1:1000, clone 3F10, Roche, Indianapolis, IN, USA).…”

Section: Immunofluorescence and Western Blot Analysismentioning

confidence: 99%

“…15 The variant RAI1-HA R1217Q was generated using the QuikChange II XL SiteDirected Mutagenesis Kit (Agilent Technologies, Santa Clara, CA, USA) utilizing the primers forward: 5¢-GCTCTCTGACCAGCCCCTCCATG-3¢ and reverse: 5¢-C ATGGAGGGGCTGGTCAGAGAGC-3¢. The variant RAI1-HA Q1389R was generated by overlapping PCR.…”

Section: Plasmid Constructsmentioning

confidence: 99%

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Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

et al. 2011

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Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of B139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. European Journal of Human Genetics (2012) 20, 148-154; doi:10.1038/ejhg.2011.167; published online 7 September 2011Keywords: Smith-Magenis syndrome; 17p11.2; RAI1; arrayCGH; mutation; deletion INTRODUCTION Smith-Magenis syndrome (SMS, MIM 182290) is a multiple congenital anomalies and intellectual disability syndrome associated with a deletion of chromosome 17p11. 2. The incidence of SMS is estimated to be B1:15 000-1:25 000 births. 1 SMS is most commonly characterized by a variable degree of intellectual disability including speech and motor delay, craniofacial and skeletal anomalies, sleep disturbance, self-injurious and attention-seeking behaviors. 1,2 Craniofacial features include brachycephaly, midface hypoplasia, tented upper lip, relative prognathism with age and deep-set and hypoteloric eyes. 3,4 Skeletal features include brachydactyly, short stature and short/ broad hands. 3,4 The behavioral phenotype includes onychotillomania, polyembolokoilamania, 'hand licking and page flipping' , 'self-hugging' and hyperactivity. 5 Sleep disturbance is present in 88% of SMS patients and is characterized by difficulty getting to sleep, frequent nocturnal awakenings, early sleep offset and daytime sleepiness with a need for daytime naps. 6,7 SMS clinical features overlap with other intellectual disability syndromes such as Prader-Willi, Williams and Down's syndromes, which often complicate its clinical diagnosis.A majority, B90%, of SMS patients have a deletion of chromosome 17p11.2 that includes the RAI1 gene. 3 The classical SMS deletions span B3.5 Mb of 17p11.2 and are present in B70% of affected individuals.

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Section: Rai1 Alterations In Patients With Features Suggestive Of Smimentioning

confidence: 93%

Section: Smith-magenis Syndrome (Sms Mim 182290mentioning

confidence: 99%

Section: Immunofluorescence and Western Blot Analysismentioning

confidence: 99%

Section: Plasmid Constructsmentioning

confidence: 99%

See 2 more Smart Citations

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

et al. 2011

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“…RAI1 has 2 putative bipartite nuclear localization signals. Functional and cellular analyses of 5 mutated forms of the human RAI1 protein indicate that the Nterminal half of the protein has transcription factor activity (within the first 1,034 amino acids), and the C-terminal half is responsible for its transportation into the nucleus [Carmona-Mora et al, 2010].…”

Section: Discussionmentioning

confidence: 99%

Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

et al. 2014

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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.

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Periventricular nodular heterotopia in Smith‐Magenis syndrome

Capra

Biancheri

Morana

et al. 2014

American J of Med Genetics Pt A

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Smith-Magenis syndrome (SMS) is caused by an interstitial microdeletion of chromosome 17p11.2. A few patients with the typical SMS phenotype have RAI1 gene mutations. The syndrome is characterized by minor craniofacial anomalies, short stature, sleep disturbances, behavioural and neurocognitive abnormalities, as well as variable multisystemic manifestations. Periventricular nodular heterotopia (PNH) is a genetically heterogeneous neuronal migration disorder characterized by subependymal heterotopic nodules, and is variably associated with other brain malformations, epileptic seizures and intellectual disability. Here we report on two patients harboring deletions of the 17p11.2 region in whom the SMS typical phenotype was associated with bilateral PNH. Our observations expand the spectrum of chromosomal rearrangements associated with PNH and indicate that abnormal neuronal migration may contribute to the neurocognitive phenotype of SMS.

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Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome

Cited by 36 publications

References 45 publications

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

Periventricular nodular heterotopia in Smith‐Magenis syndrome

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