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Human Molecular Genetics, 2000, Vol. 9, No. 1 101-108
© 2000 Oxford University Press

Profound obesity associated with a balanced translocation that disrupts the SIM1 gene

J. Lloyd Holder, Jr, Nancy F. Butte1 and Andrew R. Zinn+

Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School, 6000 Harry Hines Boulevard, Dallas, TX 75235, USA and 1Children’s Nutrition Research Center and Department of Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA

Studies of mice and humans have revealed a number of genes that when mutated result in severe obesity. We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromo- somes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced both translocation breakpoints. The translocation does not appear to affect any transcription unit on 1p, but it disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim (Single-minded), a tran- scription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (basic helix–loop–helix + period, aryl hydrocarbon receptor, Single-minded) gene family. Our subject’s trans- location separates the 5' promoter region and bHLH domain from the 3' PAS and putative transcriptional regulation domains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expressed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin 4 receptor and appear to be physiological targets of {alpha}-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.

+ To whom correspondence should be addressed. Tel: +1 214 648 1600; Fax: +1 214 648 1666; Email: azndrew.zinn@email.swmed.edu


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