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Title
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Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features
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Author
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Abstract
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| 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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Language
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English
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Source (journal)
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The journal of clinical investigation. - New York, N.Y., 1924, currens
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Publication
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New York, N.Y.
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2013
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ISSN
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0021-9738
[print]
1558-8238
[online]
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DOI
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10.1172/JCI68035
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Volume/pages
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123
:7
(2013)
, p. 3037-3041
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ISI
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000321316700031
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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