Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoic acid induced 1 gene (RAI1) is the primary causative gene for Smith-Magenis syndrome (SMS). Chromosomal deletion encompassing RAI1 or mutation in RAI1 is responsible for the majority of SMS features. Mouse models with targeted disruption of Rai1 have recapitulated overt SMS phenotypes, including craniofacial abnormalities, obesity, and neurobehavioral anomalies. Penetrance and expressivity of most phenotypes in mice were incomplete due to the mixed genetic background in which they were created. While increased penetrance of craniofacial phenotypes was observed in relatively homogeneous backgrounds, the effect of Rai1 haploinsufficiency on breeding outcome and fitness has not been studied. We analyzed mating results of Rai1+/- mice in a pure C57BL/6J background (>or=N10 generations). A significant distortion (P<0.05) of Mendelian transmission ratio with skewing against Rai1+/- mice was observed. Consequently, a decreased number of Rai1+/- pups and no Rai1-/- pups were obtained from all the breeding pairs. The decreased yield of Rai1+/- pups precluded penetrance studies of other phenotypes in these mice. However, when Rai1+/- alleles were transferred to a slightly variable (approximately 1% 129/approximately 99% C57BL/6J) genetic background expected numbers of Rai1+/- pups were obtained. Our results indicate that selection against Rai1-haploinsufficient alleles is governed primarily by modifier genes. Our data show that genetic background or modifier genes also significantly contribute to the severity of the phenotypes in SMS mouse models, mirroring the phenotypic variation observed in humans with Smith-Magenis syndrome and support the need for investigation of modifier loci for both single gene and complex genetic syndromes.
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PMID:Distorted Mendelian transmission as a function of genetic background in Rai1-haploinsufficient mice. 1911 76

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.
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PMID:Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. 2066 24

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.
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PMID:Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways. 2154 56