Dietary Regimens Modify Early Onset of Obesity in Mice Haploinsufficient for Rai1

Alaimo, Joseph T.; Hahn, Natalie H.; Mullegama, Sureni V; Elsea, Sarah H.

doi:10.1371/journal.pone.0105077

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…Receptors for the steroid hormones estrogen (ER) and androgen (AR) have an emerging role in circadian rhythms and other metabolic function regulation in the suprachiasmatic nuclei in vertebrates through alteration of brain-derived neurotropic factor ( BNDF ) expression in animal models [44–47]. Interestingly, Bdnf is also downregulated in the hypothalamus of Rai1 +/− mice, which are hyperphagic, have impaired satiety, develop obesity, and consume more food during light phase [48–50]. Since TCF20 has also been implicated in the regulation of ER- and AR-mediated transcriptional activity [10, 11, 51], we speculate that TCF20 might play a role in the regulation of circadian rhythms through steroid hormone modulation and disruption of its activity could lead to the phenotype observed in a subset of our patients.…”

Section: Discussionmentioning

confidence: 99%

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Vetrini¹,

McKee²,

Rosenfeld³

et al. 2019

Genome Med

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Background Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1 , the dosage-sensitive gene responsible for Smith–Magenis syndrome (deletion/haploinsufficiency) and Potocki–Lupski syndrome (duplication/triplosensitivity). Methods Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20 . We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. Results We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20 . The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. Conclusions TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith–Magenis syndrome. Together with previously described cases, the clinical entity of TCF20 -associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective. Electronic supplementary material The online version of this article (10.1186/s13073-019-0623-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Vetrini¹,

McKee²,

Rosenfeld³

et al. 2019

Genome Med

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“…Importantly, SMS patients show higher levels of total cholesterol, high-density lipoprotein (HDL), lowdensity lipoprotein (LDL), and TGs 61 . The most widely accepted hypothesis is that RAI1 haploinsu ciency causes compulsive hyperphagic behavior, which is the main cause of obesity in patients, an aspect replicated in animal models of disease 2,6,58,62,63 . Our ndings, however, reveal an alternative and possibly coexisting scenario: SMS cells are fat and have a lipid deregulation driven not only by nutrient availability but also by TG accumulation in LDs.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome

Turco

Giovenale

Sireno

et al. 2022

Preprint

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Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance. There is no therapy to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are not known. Here, we generated and characterized primary cells derived from four SMS patients, two carrying SMS-del and two carrying RAI1 point mutations, and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we show altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and a block of autophagic flux. SMS cells show increased cell death associated with mitochondrial pathology and reactive oxygen species production. Treatment with N-acetylcysteine reduces cell death and lipid accumulation, suggesting a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

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“…Total RNA was isolated according to standard methods (Invitrogen, Carlsbad, CA), quantified using the NanoDrop® ND-100 Spectrophotometer, and reverse transcribed with qSCRIPT cDNA SuperMix (Quanta Biosciences, Inc., Gaithersburg, MD) according to the manufacturer’s instructions. Real-time quantitative PCR (RT-qPCR) was performed as previously described [ 16 ]. Briefly, Taqman probes (Life Technologies, Carlsbad, CA) for RAI1 (Hs01554690_m1), FLCN (Hs00376065_m1), PEMT (Hs00540979_m1), and GAPDH (Hs9999905_m1) were used.…”

Section: Methodsmentioning

confidence: 99%

Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki–Lupski syndrome diagnosis

et al. 2015

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The identification of structural variants of uncertain clinical significance is increasing; however, studies delineating the functional consequence of these variants in the pathogenicity of phenotypic features are lacking. Understanding the consequence of structural variants such as copy number alterations and their role in gene expression changes is paramount in order to perform a comprehensive analysis of genetic effects on phenotypic variation and disease. RAI1 is a dosage-sensitive essential neurodevelopmental gene. Copy number loss of RAI1 results in Smith-Magenis syndrome while copy number gain results in Potocki-Lupski syndrome. Here, we present a case of a six year old female with a newly identified maternally inherited copy number loss that lies within the Smith-Magenis syndrome common deletion region, but RAI1 copy number is normal. Integration of the Encyclopedia of DNA Elements (ENCODE) data at the affected region suggests that the deletion disrupts several cis-acting regulatory elements upstream of RAI1, such as multiple repressor sites and an insulator region. Gene expression studies revealed that both the proband and the mother have significantly elevated RAI1 mRNA levels suggesting that the structural variant alters gene expression regulation. The proband and the mother both have some features of Potocki-Lupski syndrome, while the child appears to be more affected with autistic-like features. Overall, our work demonstrates that the integration of ENCODE data with structural variants of uncertain significance aids in delineating a functional consequence to a genomic aberration and subsequent diagnosis.

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Dietary Regimens Modify Early Onset of Obesity in Mice Haploinsufficient for Rai1

Cited by 14 publications

References 35 publications

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

Retinoic acid-induced 1 gene haploinsufficiency alters lipid metabolism and causes autophagy defects in Smith-Magenis syndrome

Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki–Lupski syndrome diagnosis

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