The Experts below are selected from a list of 25590 Experts worldwide ranked by ideXlab platform
Sarah H Elsea - One of the best experts on this subject based on the ideXlab platform.
-
nonrecurrent pmp22 RAI1 contiguous gene deletions arise from replication based mechanisms and result in smith magenis syndrome with evident peripheral neuropathy
Human Genetics, 2016Co-Authors: Bo Yuan, Sarah H Elsea, Lorraine Potocki, Juanita Neira, Tamar Harel, Pengfei Liu, Ignacio Briceno, Alberto Gomez, James R LupskiAbstract:Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.
-
Dietary Regimens Modify Early Onset of Obesity in Mice Haploinsufficient
2014Co-Authors: For Rai, Joseph T. Alaimo, Natalie H. Hahn, Sureni V. Mullegama, Sarah H ElseaAbstract:Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of RAI1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant RAI1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J RAI1+/2 mice with FVB/NJ to create F1 RAI1+/2 offspring in a mixed genetic background ameliorates both fecundity and RAI1 allele transmission phenotypes. These findings suggest that the mixed background provides a more robust platform for breeding and larger phenotypic studies. We also characterized the effect of dietary intake on RAI1+/2 mouse growth during adolescent and early adulthood developmental stages. Animals fed a high carbohydrate or a high fat diet gained weight at a significantly faster rate than their wild type littermates. Both high fat and high carbohydrate fed RAI1+/2 mice also had an increase in body fat and altered fat distribution patterns. Interestingly, RAI1+/2 mice fed different diets did not display altered fasting blood glucose levels. These results suggest that dietary regimens are extremely important for individuals with Smith- Magenis syndrome and that food high in fat and carbohydrates may exacerbate obesity outcomes
-
smith magenis syndrome results in disruption of clock gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity
American Journal of Human Genetics, 2012Co-Authors: Sureni V. Mullegama, Stephen R Williams, Deborah L Zies, Mike Grotewiel, Sarah H ElseaAbstract:Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity, neurobehavioral abnormalities, and a disrupted circadian sleep-wake pattern. An inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in individuals with SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of RAI1, support SMS as a circadian-rhythm-dysfunction disorder. However, the molecular cause of the circadian defect in SMS has not been described. The circadian oscillator temporally orchestrates metabolism, physiology, and behavior largely through transcriptional modulation. Data support RAI1 as a transcriptional regulator, but the genes it might regulate are largely unknown. Investigation into the role that RAI1 plays in the regulation of gene transcription and circadian maintenance revealed that RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Data further show that haploinsufficiency of RAI1 and RAI1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. These data suggest that heterozygous mutation of RAI1 and RAI1 leads to a disrupted circadian rhythm and thus results in an abnormal sleep-wake cycle, which can contribute to an abnormal feeding pattern and dependent cognitive performance. Finally, we conclude that RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator.
-
smith magenis syndrome haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways
Expert Reviews in Molecular Medicine, 2011Co-Authors: Sarah H Elsea, Stephen R WilliamsAbstract:Smith-Magenis syndrome (SMS) is a complex neurobehavioural disorder characterised by intellectual disability, self-injurious behaviours, sleep disturbance, obesity, and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. Functional studies based on the hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. Here, we review the clinical and molecular features of SMS and explore more recent studies supporting possible therapeutic strategies for behavioural management.
-
RAI1 haploinsufficiency causes reduced bdnf expression resulting in hyperphagia obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome
Human Molecular Genetics, 2010Co-Authors: Brooke Burns, Santhosh Girirajan, Kristie Schmidt, Stephen R Williams, Sun Kim, Sarah H ElseaAbstract:Smith-Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for RAI1. Data show that RAI1(+/-) mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with RAI1(+/-) female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the RAI1(+/-) mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the RAI1(+/-) mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that RAI1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of RAI1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.
James R Lupski - One of the best experts on this subject based on the ideXlab platform.
-
nonrecurrent pmp22 RAI1 contiguous gene deletions arise from replication based mechanisms and result in smith magenis syndrome with evident peripheral neuropathy
Human Genetics, 2016Co-Authors: Bo Yuan, Sarah H Elsea, Lorraine Potocki, Juanita Neira, Tamar Harel, Pengfei Liu, Ignacio Briceno, Alberto Gomez, James R LupskiAbstract:Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.
-
circadian abnormalities in mouse models of smith magenis syndrome evidence for involvement of RAI1
American Journal of Medical Genetics Part A, 2013Co-Authors: Melanie Lacaria, James R LupskiAbstract: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. © 2013 Wiley Periodicals, Inc.
-
abnormal circadian rhythm of melatonin in smith magenis syndrome patients with RAI1 point mutations
American Journal of Medical Genetics Part A, 2011Co-Authors: Philip M Boone, James R Lupski, Russel J Reiter, Daniel G Glaze, Dun Xian Tan, Lorraine PotockiAbstract:To the Editor: Smith-Magenis syndrome (SMS; OMIM 182290) is a genomic disorder characterized by multiple congenital anomalies, developmental delay, intellectual disability, and a distinct behavioral phenotype including aggressiveness, self-injury, and sleep disturbances [Edelman et al., 2007; Greenberg et al., 1996; Smith et al., 1986]. Most patients with SMS (~75%) harbor a recurrent 3.7 megabase (Mb) microdeletion of 17p11.2, mediated by flanking low copy repeats (LCRs) [Bi et al., 2003; Chen et al., 1997; Potocki et al., 2003; Shaw et al., 2002]. . The retinoic acid-induced gene 1 (RAI1) is one of approximately 25 genes within the SMS critical region [Bi et al., 2002; Vlangos et al., 2003], and heterozygous RAI1 mutations have been reported in individuals who resemble SMS patients clinically, but who lack a 17p11.2 deletion; thus, haploinsufficiency of RAI1 is considered the cause of most of the manifestations of SMS [Bi et al., 2004, 2006; Girirajan et al., 2005, 2006; Slager et al., 2003]. Nonetheless, the prevalence of some phenotypes, for example cardiovascular malformations and hearing loss, differ between SMS deletion patients and those with RAI1 point mutations [Edelman et al., 2007; Girirajan et al., 2006], suggesting that other loci within 17p11.2 and/or genomic rearrangement itself [Ricard et al., 2010] may contribute to or modify the SMS phenotype. Subjective sleep disturbances are well documented in SMS [Smith et al., 1998]. Additionally, objective sleep disturbances, including multiple awakenings, decreased or increased percentage of REM sleep, and decreased total sleep time have been detected by polysomnography [Greenberg et al., 1996; Potocki et al., 2000] and actigraphy [De Leersnyder et al., 2001a; Gropman et al., 2006]. Inverted circadian rhythmicity of melatonin in SMS deletion patients has also been reported [De Leersnyder et al., 2001a; Potocki et al., 2000]. Persons with RAI1 mutations also have a high rate of subjective sleep disturbance (14 of 14 subjects described in [Bi et al., 2004, 2006; Girirajan et al., 2005, 2006; Slager et al., 2003]), statistically equivalent to that of individuals with the common (3.7 Mb) SMS deletion (39/39 in [Potocki et al., 2003]). It is unknown if RAI1 mutations lead to an alteration of melatonin rhythmicity. Given melatonin’s role in sleep-wake patterning [Brzezinski 1997], we hypothesized that haploinsufficiency of RAI1 alone may lead to inversion of melatonin rhythmicity, potentially explaining disordered sleep in individuals with this genotype. In this report we document an inverted circadian rhythm of melatonin in a child and an adult who each harbor a RAI1 mutation. Individuals with clinical suspicion for SMS were enrolled in a multidisciplinary clinical study, approved by the Institutional Review Board of Baylor College of Medicine, at Texas Children’s Hospital in Houston, USA; informed consent was provided in each case. This comprehensive clinical protocol included physical examination, polysomnography, and urine collection to measure 6-sulfatoxymelatonin (6-hydroxymelatonin sulfate, aMT6s), the major excreted metabolite of melatonin [Reiter, 1991; Potocki et al., 2000]. Molecular characterization and some phenotypic details of these subjects have been described previously [Bi et al., 2004, 2006; Chen et al., 1997; Liburd et al., 2001; Potocki et al., 2000, 2003; Slager et al., 2003]. Briefly, individuals with clinical suspicion for SMS were screened by FISH for deletions on chromosome 17p11.2. Subjects who did not have a del(17)(p11.2p11.2) by FISH underwent sequencing of the RAI1 gene, which identified a heterozygous nonsense mutation in subject 1106, an 11-year-old girl [Bi et al., 2004], and a heterozygous frameshift mutation in subject 526 (listed as SMS156 in Slager et al., [2003]), a 27-year-old woman. Both of these subjects experienced subjective sleep disturbances by parental report. Subject 1106 took melatonin (6 mg at bedtime), which was discontinued 3 weeks prior to the study. Subject 526 took no medications. Subjects were evaluated in the sleep laboratory at Texas Children’s Hospital [Potocki et al., 2000]. Briefly, the subjects underwent continuous 21-channel polysomnographic monitoring as well as in-person and video behavioral monitoring for one night. Sleep staging was determined using standard criteria. A multiple sleep latency test (MSLT) was performed the following day. The subjects’ spontaneously voided urine was collected at several time points and analyzed for aMT6s concentration [Potocki et al., 2000]. Urine from a healthy girl and a healthy man, analyzed similarly, served as controls [Reiter et al., 1996]. Both subjects with RAI1 mutations demonstrated sleep disturbances by polysomnography similar to those of subjects with the SMS common deletion (Table I). MSLT findings were normal (data not shown). The rhythm of urinary aMT6s concentration, a surrogate for serum melatonin concentration [Reiter, 1991], was found to be altered in both subjects with RAI1 mutations (Fig. 1). A normal circadian rhythm of urinary aMT6s concentration peaks in the early morning (Fig. 1a), resulting from a nocturnal maximum of melatonin production. In contrast, the urinary aMT6s concentration in both child (1106) and adult (526) with RAI1 point mutations (Fig. 1b) displayed an inverted pattern with a daytime maximum, similar to age-matched subjects with the SMS common deletion (1206 and 1123, respectively [Potocki et al., 2000]) shown for comparison (Fig. 1c). As subjects 1106 and 1206 and the younger control individual are children, their overall levels of aMT6s are expectedly higher than those of the adult control individual or of subjects 526 and 1123 [Waldhauser et al., 1984]. Figure 1 Melatonin rhythmicity is altered in RAI1 mutation patients Table I Sleep abnormalities in four subjects. Subjective sleep disturbance is common in SMS, corroborated by objective abnormalities on polysomnography [Greenberg et al., 1991, 1996]. SMS deletion patients have been reported to have an inverted circadian rhythm of melatonin [De Leersnyder et al., 2001a; Potocki et al., 2000]. Our results indicate that SMS patients with mutations in RAI1, a gene mapping within the SMS critical region, have similarly altered melatonin rhythmicity. It is unknown whether RAI1 is the only gene within the SMS critical region for which reduced dosage leads to altered melatonin rhythmicity. For example, RASD1, also located within the SMS critical region, is a modulator of the responsiveness of the core (suprachiasmatic nucleus) circadian clock to photic and nonphotic inputs [Cheng et al., 2004]. It is also unknown 1) whether alteration of melatonin rhythmicity is solely responsible for the sleep disturbances in SMS, 2) whether this alteration accompanies or causes similar disturbance of the core circadian clock, peripheral clocks, or other clock outputs, and 3) most basically, whether it constitutes a true inversion of rhythmicity or simply a phase advance or delay of approximately half of a day. Properly-timed exogenous administration of melatonin can shift human circadian rhythms [Lewy et al., 1992] and promote and quantitatively improve sleep in adults with sleep disorders and in children with neurodevelopmental difficulties [Brzezinski 1997; Jan et al., 2000; Zhdanova and Wurtman 1997]. Thus, exogenous melatonin has been given nocturnally to SMS patients to induce and improve sleep, in some cases in combination with diurnal β1-adrenergic antagonist administration to inhibit daytime melatonin production and resultant daytime sleepiness [Carpizo et al., 2006; De Leersnyder et al., 2001b, 2003, 2006]. The success of this regimen in a small number of patients is promising, and our results indicate that, in addition to SMS deletion patients, it is rational that RAI1 mutation patients may also benefit from such treatments.
-
penetrance of craniofacial anomalies in mouse models of smith magenis syndrome is modified by genomic sequence surrounding RAI1 not all null alleles are alike
American Journal of Human Genetics, 2007Co-Authors: Jiong Yan, James R LupskiAbstract:Craniofacial abnormality is one of the major clinical manifestations of Smith-Magenis syndrome (SMS). Previous analyses in a mixed genetic background of several SMS mouse models—including Df(11)17 /+ and Df(11)17-1 /+, which have 2-Mb and 590-kb deletions, respectively, and RAI1 −/+ —revealed that the penetrance of the craniofacial phenotype appears to be influenced by deletion size and genetic background. We generated an additional strain with a 1-Mb deletion intermediate in size between the two described above. Remarkably, the penetrance of its craniofacial anomalies in the mixed background was between those of Df(11)17 and Df(11)17-1. We further analyzed the deletion mutations and the RAI1 −/+ allele in a pure C57BL/6 background, to control for nonlinked modifier loci. The penetrance of the craniofacial anomalies was markedly increased for all the strains in comparison with the mixed background. Mice with Df(11)17 and Df(11)17-1 deletions had a similar penetrance, suggesting that penetrance may be less influenced by deletion size, whereas that of RAI1 −/+ mice was significantly lower than that of the deletion strains. We hypothesize that potential trans -regulatory sequence(s) or gene(s) that reside within the 590-kb genomic interval surrounding RAI1 are the major modifying genetic element(s) affecting the craniofacial penetrance. Moreover, we confirmed the influence of genetic background and different deletion sizes on the phenotype. The complicated control of the penetrance for one phenotype in SMS mouse models provides tools to elucidate molecular mechanisms for penetrance and clearly shows that a null allele caused by chromosomal deletion can have different phenotypic consequences than one caused by gene inactivation.
-
RAI1 point mutations cag repeat variation and snp analysis in non deletion smith magenis syndrome
American Journal of Medical Genetics Part A, 2006Co-Authors: Mustafa G Saifi, Sarah H Elsea, Santhosh Girirajan, Lorraine Potocki, Barbara Szomju, Xin Shi, Helen V Firth, Ellen R Magenis, James R LupskiAbstract:Smith–Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother. © 2006 Wiley-Liss, Inc.
Santhosh Girirajan - One of the best experts on this subject based on the ideXlab platform.
-
molecular basis for phenotypic similarity of genetic disorders
Genome Medicine, 2019Co-Authors: Vijay Kumar Pounraja, Santhosh GirirajanAbstract:The contribution of distinct genes to overlapping phenotypes suggests that such genes share ancestral origins, membership of disease pathways, or molecular functions. A recent study by Liu and colleagues identified mutations in TCF20, a paralog of RAI1, among individuals manifesting a novel syndrome that has phenotypes similar to those of Smith-Magenis syndrome (a disorder caused by disruption of RAI1). This study highlights how structural similarity among genes contributes to shared phenotypes, and shows how this relationship can contribute to our understanding of the genetic basis of complex disorders.
-
RAI1 haploinsufficiency causes reduced bdnf expression resulting in hyperphagia obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome
Human Molecular Genetics, 2010Co-Authors: Brooke Burns, Santhosh Girirajan, Kristie Schmidt, Stephen R Williams, Sun Kim, Sarah H ElseaAbstract:Smith-Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for RAI1. Data show that RAI1(+/-) mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with RAI1(+/-) female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the RAI1(+/-) mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the RAI1(+/-) mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that RAI1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of RAI1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.
-
a functional network module for smith magenis syndrome
Clinical Genetics, 2009Co-Authors: Santhosh Girirajan, Christopher Blanchard, H T Truong, Sarah H ElseaAbstract:Disorders with overlapping diagnostic features are grouped into a network module. Based on phenotypic similarities or differential diagnoses, it is possible to identify functional pathways leading to individual features. We generated a Smith–Magenis syndrome (SMS)-specific network module utilizing patient clinical data, text mining from the Online Mendelian Inheritance in Man database, and in vitro functional analysis. We tested our module by functional studies based on a hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes, which are altered due to RAI1 haploinsufficiency. A preliminary genome-wide gene expression study was performed using microarrays on RAI1 haploinsufficient cells created by RNAi-based ∼50% knockdown of RAI1 in HEK293T cells. The top dysregulated genes were involved in growth signaling and insulin sensitivity, neuronal differentiation, lipid biosynthesis and fat mobilization, circadian activity, behavior, renal, cardiovascular and skeletal development, gene expression, and cell-cycle regulation and recombination, reflecting the spectrum of clinical features observed in SMS. Validation using real-time quantitative reverse transcriptase polymerase chain reaction confirmed the gene expression profile of 75% of the selected genes analyzed in both HEK293T RAI1 knockdown cells and SMS lymphoblastoid cell lines. Overall, these data support a method for identifying genes and pathways responsible for individual clinical features in a complex disorder such as SMS.
-
smith magenis syndrome
European Journal of Human Genetics, 2008Co-Authors: Sarah H Elsea, Santhosh GirirajanAbstract:Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder caused by haploinsufficiency of the retinoic acid-induced 1 (RAI1) gene on chromosome 17p11.2. Diagnostic strategies include molecular identification of a 17p11.2 microdeletion encompassing RAI1 or a mutation in RAI1. G-banding and fluorescent in situ hybridization (FISH) are the classical methods used to detect the SMS deletions, while multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR are the newer, cost-effective, and high-throughput technologies. Most SMS features are due to RAI1 haploinsufficiency, while the variability and severity of the disorder are modified by other genes in the 17p11.2 region. The functional role for RAI1 is not completely understood, but it is likely involved in transcription, based on homology and preliminary studies. Management of SMS is primarily a multidisciplinary approach and involves treatment for sleep disturbance, speech and occupational therapies, minor medical interventions, and management of behaviors.
-
RAI1 point mutations cag repeat variation and snp analysis in non deletion smith magenis syndrome
American Journal of Medical Genetics Part A, 2006Co-Authors: Mustafa G Saifi, Sarah H Elsea, Santhosh Girirajan, Lorraine Potocki, Barbara Szomju, Xin Shi, Helen V Firth, Ellen R Magenis, James R LupskiAbstract:Smith–Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother. © 2006 Wiley-Liss, Inc.
Lorraine Potocki - One of the best experts on this subject based on the ideXlab platform.
-
nonrecurrent pmp22 RAI1 contiguous gene deletions arise from replication based mechanisms and result in smith magenis syndrome with evident peripheral neuropathy
Human Genetics, 2016Co-Authors: Bo Yuan, Sarah H Elsea, Lorraine Potocki, Juanita Neira, Tamar Harel, Pengfei Liu, Ignacio Briceno, Alberto Gomez, James R LupskiAbstract:Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.
-
abnormal circadian rhythm of melatonin in smith magenis syndrome patients with RAI1 point mutations
American Journal of Medical Genetics Part A, 2011Co-Authors: Philip M Boone, James R Lupski, Russel J Reiter, Daniel G Glaze, Dun Xian Tan, Lorraine PotockiAbstract:To the Editor: Smith-Magenis syndrome (SMS; OMIM 182290) is a genomic disorder characterized by multiple congenital anomalies, developmental delay, intellectual disability, and a distinct behavioral phenotype including aggressiveness, self-injury, and sleep disturbances [Edelman et al., 2007; Greenberg et al., 1996; Smith et al., 1986]. Most patients with SMS (~75%) harbor a recurrent 3.7 megabase (Mb) microdeletion of 17p11.2, mediated by flanking low copy repeats (LCRs) [Bi et al., 2003; Chen et al., 1997; Potocki et al., 2003; Shaw et al., 2002]. . The retinoic acid-induced gene 1 (RAI1) is one of approximately 25 genes within the SMS critical region [Bi et al., 2002; Vlangos et al., 2003], and heterozygous RAI1 mutations have been reported in individuals who resemble SMS patients clinically, but who lack a 17p11.2 deletion; thus, haploinsufficiency of RAI1 is considered the cause of most of the manifestations of SMS [Bi et al., 2004, 2006; Girirajan et al., 2005, 2006; Slager et al., 2003]. Nonetheless, the prevalence of some phenotypes, for example cardiovascular malformations and hearing loss, differ between SMS deletion patients and those with RAI1 point mutations [Edelman et al., 2007; Girirajan et al., 2006], suggesting that other loci within 17p11.2 and/or genomic rearrangement itself [Ricard et al., 2010] may contribute to or modify the SMS phenotype. Subjective sleep disturbances are well documented in SMS [Smith et al., 1998]. Additionally, objective sleep disturbances, including multiple awakenings, decreased or increased percentage of REM sleep, and decreased total sleep time have been detected by polysomnography [Greenberg et al., 1996; Potocki et al., 2000] and actigraphy [De Leersnyder et al., 2001a; Gropman et al., 2006]. Inverted circadian rhythmicity of melatonin in SMS deletion patients has also been reported [De Leersnyder et al., 2001a; Potocki et al., 2000]. Persons with RAI1 mutations also have a high rate of subjective sleep disturbance (14 of 14 subjects described in [Bi et al., 2004, 2006; Girirajan et al., 2005, 2006; Slager et al., 2003]), statistically equivalent to that of individuals with the common (3.7 Mb) SMS deletion (39/39 in [Potocki et al., 2003]). It is unknown if RAI1 mutations lead to an alteration of melatonin rhythmicity. Given melatonin’s role in sleep-wake patterning [Brzezinski 1997], we hypothesized that haploinsufficiency of RAI1 alone may lead to inversion of melatonin rhythmicity, potentially explaining disordered sleep in individuals with this genotype. In this report we document an inverted circadian rhythm of melatonin in a child and an adult who each harbor a RAI1 mutation. Individuals with clinical suspicion for SMS were enrolled in a multidisciplinary clinical study, approved by the Institutional Review Board of Baylor College of Medicine, at Texas Children’s Hospital in Houston, USA; informed consent was provided in each case. This comprehensive clinical protocol included physical examination, polysomnography, and urine collection to measure 6-sulfatoxymelatonin (6-hydroxymelatonin sulfate, aMT6s), the major excreted metabolite of melatonin [Reiter, 1991; Potocki et al., 2000]. Molecular characterization and some phenotypic details of these subjects have been described previously [Bi et al., 2004, 2006; Chen et al., 1997; Liburd et al., 2001; Potocki et al., 2000, 2003; Slager et al., 2003]. Briefly, individuals with clinical suspicion for SMS were screened by FISH for deletions on chromosome 17p11.2. Subjects who did not have a del(17)(p11.2p11.2) by FISH underwent sequencing of the RAI1 gene, which identified a heterozygous nonsense mutation in subject 1106, an 11-year-old girl [Bi et al., 2004], and a heterozygous frameshift mutation in subject 526 (listed as SMS156 in Slager et al., [2003]), a 27-year-old woman. Both of these subjects experienced subjective sleep disturbances by parental report. Subject 1106 took melatonin (6 mg at bedtime), which was discontinued 3 weeks prior to the study. Subject 526 took no medications. Subjects were evaluated in the sleep laboratory at Texas Children’s Hospital [Potocki et al., 2000]. Briefly, the subjects underwent continuous 21-channel polysomnographic monitoring as well as in-person and video behavioral monitoring for one night. Sleep staging was determined using standard criteria. A multiple sleep latency test (MSLT) was performed the following day. The subjects’ spontaneously voided urine was collected at several time points and analyzed for aMT6s concentration [Potocki et al., 2000]. Urine from a healthy girl and a healthy man, analyzed similarly, served as controls [Reiter et al., 1996]. Both subjects with RAI1 mutations demonstrated sleep disturbances by polysomnography similar to those of subjects with the SMS common deletion (Table I). MSLT findings were normal (data not shown). The rhythm of urinary aMT6s concentration, a surrogate for serum melatonin concentration [Reiter, 1991], was found to be altered in both subjects with RAI1 mutations (Fig. 1). A normal circadian rhythm of urinary aMT6s concentration peaks in the early morning (Fig. 1a), resulting from a nocturnal maximum of melatonin production. In contrast, the urinary aMT6s concentration in both child (1106) and adult (526) with RAI1 point mutations (Fig. 1b) displayed an inverted pattern with a daytime maximum, similar to age-matched subjects with the SMS common deletion (1206 and 1123, respectively [Potocki et al., 2000]) shown for comparison (Fig. 1c). As subjects 1106 and 1206 and the younger control individual are children, their overall levels of aMT6s are expectedly higher than those of the adult control individual or of subjects 526 and 1123 [Waldhauser et al., 1984]. Figure 1 Melatonin rhythmicity is altered in RAI1 mutation patients Table I Sleep abnormalities in four subjects. Subjective sleep disturbance is common in SMS, corroborated by objective abnormalities on polysomnography [Greenberg et al., 1991, 1996]. SMS deletion patients have been reported to have an inverted circadian rhythm of melatonin [De Leersnyder et al., 2001a; Potocki et al., 2000]. Our results indicate that SMS patients with mutations in RAI1, a gene mapping within the SMS critical region, have similarly altered melatonin rhythmicity. It is unknown whether RAI1 is the only gene within the SMS critical region for which reduced dosage leads to altered melatonin rhythmicity. For example, RASD1, also located within the SMS critical region, is a modulator of the responsiveness of the core (suprachiasmatic nucleus) circadian clock to photic and nonphotic inputs [Cheng et al., 2004]. It is also unknown 1) whether alteration of melatonin rhythmicity is solely responsible for the sleep disturbances in SMS, 2) whether this alteration accompanies or causes similar disturbance of the core circadian clock, peripheral clocks, or other clock outputs, and 3) most basically, whether it constitutes a true inversion of rhythmicity or simply a phase advance or delay of approximately half of a day. Properly-timed exogenous administration of melatonin can shift human circadian rhythms [Lewy et al., 1992] and promote and quantitatively improve sleep in adults with sleep disorders and in children with neurodevelopmental difficulties [Brzezinski 1997; Jan et al., 2000; Zhdanova and Wurtman 1997]. Thus, exogenous melatonin has been given nocturnally to SMS patients to induce and improve sleep, in some cases in combination with diurnal β1-adrenergic antagonist administration to inhibit daytime melatonin production and resultant daytime sleepiness [Carpizo et al., 2006; De Leersnyder et al., 2001b, 2003, 2006]. The success of this regimen in a small number of patients is promising, and our results indicate that, in addition to SMS deletion patients, it is rational that RAI1 mutation patients may also benefit from such treatments.
-
RAI1 point mutations cag repeat variation and snp analysis in non deletion smith magenis syndrome
American Journal of Medical Genetics Part A, 2006Co-Authors: Mustafa G Saifi, Sarah H Elsea, Santhosh Girirajan, Lorraine Potocki, Barbara Szomju, Xin Shi, Helen V Firth, Ellen R Magenis, James R LupskiAbstract:Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother.
-
RAI1 point mutations cag repeat variation and snp analysis in non deletion smith magenis syndrome
American Journal of Medical Genetics Part A, 2006Co-Authors: Mustafa G Saifi, Sarah H Elsea, Santhosh Girirajan, Lorraine Potocki, Barbara Szomju, Xin Shi, Helen V Firth, Ellen R Magenis, James R LupskiAbstract:Smith–Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother. © 2006 Wiley-Liss, Inc.
-
mutations of RAI1 a phd containing protein in nondeletion patients with smith magenis syndrome
Human Genetics, 2004Co-Authors: Mustafa G Saifi, Katherina Walz, James R Lupski, Christine J Shaw, Patricia Fonseca, Meredith Wilson, Lorraine PotockiAbstract:Smith-Magenis syndrome (SMS) is a mental retardation/multiple congenital anomalies disorder associated with a heterozygous ~4-Mb deletion in 17p11.2. Patients with SMS show variability in clinical phenotype despite a common deletion found in >75–80% of patients. Recently, point mutations in the retinoic acid induced 1 (RAI1) gene, which lies within the SMS critical interval, were identified in three patients with many SMS features in whom no deletion was detected. It is not clear if the entire SMS phenotype can be accounted for by RAI1 haploinsufficiency, nor has the precise function of RAI1 been delineated. We report two novel RAI1 mutations, one frameshift and one nonsense allele, in nondeletion SMS patients. Comparisons of the clinical features in these two patients, three of the previously reported RAI1 point mutation cases, and the patients with a common deletion suggest that the majority of the clinical features in SMS result from RAI1 mutation, although phenotypic variability exists even among the individuals with RAI1 point mutations. Bioinformatics analyses of RAI1 and comparative genomics between human and mouse orthologues revealed a zinc finger-like plant homeo domain (PHD) at the carboxyl terminus that is conserved in the trithorax group of chromatin-based transcription regulators. These findings suggest RAI1 is involved in transcriptional control through a multi-protein complex whose function may be altered in individuals with SMS.
Katherina Walz - One of the best experts on this subject based on the ideXlab platform.
-
RAI1 Haploinsufficiency Is Associated with Social Abnormalities in Mice
MDPI AG, 2017Co-Authors: Nalini R Rao, Juan I. Young, Clemer Abad, Irene C. Perez, Anand K Srivastava, Katherina WalzAbstract:Background: Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of RAI1 are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Methods: To investigate the relationship between RAI1 and social impairment, we evaluated the RAI1+/− mice with a battery of tests to address social behavior in mice. Results: We found that the mutant mice showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors when compared to wild type littermates. Conclusions: These findings suggest that RAI1 contributes to social behavior in mice, and prompt it as a candidate gene for the social behaviors observed in Smith-Magenis Syndrome patients
-
RAI1 Transcription Factor Activity Is Impaired in Mutants Associated with Smith-Magenis Syndrome
2016Co-Authors: Paulina Carmona-mora, Cesar P. Canales, Lei Cao, Juan I. Young, Irene C. Perez, K. Srivastava, Katherina WalzAbstract: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 tota
-
RAI1 transcription factor activity is impaired in mutants associated with smith magenis syndrome
PLOS ONE, 2012Co-Authors: Paulina Carmonamora, Katherina Walz, Cesar P. Canales, Lei Cao, Juan I. Young, Irene C. Perez, Anand K SrivastavaAbstract: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.
-
Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome
BMC Molecular Biology, 2010Co-Authors: Paulina Carmona-mora, Carolina Encina, Cesar P. Canales, Lei Cao, Jessica Molina, Pamela Kairath, Juan I. Young, Katherina WalzAbstract:Background 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.
-
mutations of RAI1 a phd containing protein in nondeletion patients with smith magenis syndrome
Human Genetics, 2004Co-Authors: Mustafa G Saifi, Katherina Walz, James R Lupski, Christine J Shaw, Patricia Fonseca, Meredith Wilson, Lorraine PotockiAbstract:Smith-Magenis syndrome (SMS) is a mental retardation/multiple congenital anomalies disorder associated with a heterozygous ~4-Mb deletion in 17p11.2. Patients with SMS show variability in clinical phenotype despite a common deletion found in >75–80% of patients. Recently, point mutations in the retinoic acid induced 1 (RAI1) gene, which lies within the SMS critical interval, were identified in three patients with many SMS features in whom no deletion was detected. It is not clear if the entire SMS phenotype can be accounted for by RAI1 haploinsufficiency, nor has the precise function of RAI1 been delineated. We report two novel RAI1 mutations, one frameshift and one nonsense allele, in nondeletion SMS patients. Comparisons of the clinical features in these two patients, three of the previously reported RAI1 point mutation cases, and the patients with a common deletion suggest that the majority of the clinical features in SMS result from RAI1 mutation, although phenotypic variability exists even among the individuals with RAI1 point mutations. Bioinformatics analyses of RAI1 and comparative genomics between human and mouse orthologues revealed a zinc finger-like plant homeo domain (PHD) at the carboxyl terminus that is conserved in the trithorax group of chromatin-based transcription regulators. These findings suggest RAI1 is involved in transcriptional control through a multi-protein complex whose function may be altered in individuals with SMS.
