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Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features
Amélie Bonnefond1, Anne Raimondo, Fanny Stutzmann
1European Genomic Institute for Diabetes, Lille Pasteur Institute, Lille, France.
Insights
Genetic variants in the SIM1 gene are strongly linked to severe obesity. Loss-of-function mutations in SIM1 contribute to obesity risk, independent of Prader-Willi-like syndrome features, highlighting its role in weight regulation.
Area of Science:
- Genetics
- Obesity Research
- Molecular Biology
Background:
- Sim1 haploinsufficiency in mice causes obesity and brain abnormalities.
- Human chromosome 6q16 abnormalities, including SIM1, are linked to Prader-Willi-like syndrome in obese children.
- The direct role of SIM1 in human obesity remained unconfirmed.
Purpose of the Study:
- To investigate the association between SIM1 gene variants and severe obesity in humans.
- To determine the functional impact of identified SIM1 variants on transcriptional activity.
- To establish a link between SIM1 loss-of-function and obesity risk.
Main Methods:
- Sequencing of the SIM1 gene in cohorts of children with Prader-Willi-like syndrome features, early-onset obesity, morbidly obese adults, and controls.
- Analysis of intra-family obesity risk in carriers of rare SIM1 variants.
- Functional assessment of SIM1 variants using luciferase gene reporter assays in stable cell lines.
Main Results:
- Identified 8 rare SIM1 variants in children with Prader-Willi-like syndrome features and morbidly obese adults.
- Demonstrated a significant contribution of rare SIM1 variants to intra-family obesity risk.
- Found that 3 variants (p.T46R, p.H323Y, p.T714A) exhibited strong loss-of-function effects and were associated with high intra-family obesity risk.
Conclusions:
- Genetic and functional studies confirm a strong link between SIM1 loss-of-function and severe obesity.
- SIM1 plays a crucial role in regulating body weight, with its dysfunction contributing to obesity independently of Prader-Willi-like features.
Abstract:
Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.
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