Loss of function mutations in SIM1 are responsible for severe obesity and Prader-Willi-like syndrome

Posted by & filed under Part 18: HORMONES.

Two independent groups have published on the July issue of the Journal of Clinical Investigation that loss of function mutations in the SIM1 gene result in severe obesity and in a Prader-Willi-like phenotype.

SIM1 is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. 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. The two groups found mutations in the SIM1 gene in severly obese patients and one group identified SIM1 mutations in patients with features of Prader-Willi syndrome including developmental delay, intellectual disability and hypogonadism. SIM1 mutants resulted in reduced transcriptional activities in gene reporter assays.

Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw, Philippe Froguel. Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features. JCI, Volume 123, Issue 7; Page 3037
Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keogh, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O’Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whitelaw, I. Sadaf Farooqi. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. JCI, Volume 123, Issue 7; Page 3042
Posted by Nicola Brunetti-Pierri, MD, FACMG

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