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

J. Lloyd Holder, Nancy F. Butte, Andrew R. Zinn

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Abstract

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 chromosomes 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 transcription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (hasic 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 α-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.

Original languageEnglish (US)
Pages (from-to)101-108
Number of pages8
JournalHuman Molecular Genetics
Volume9
Issue number1
StatePublished - 2000

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Receptor, Melanocortin, Type 4
Morbid Obesity
Obesity
Eating
Genes
Melanocyte-Stimulating Hormones
Haploinsufficiency
Aryl Hydrocarbon Receptors
Supraoptic Nucleus
Paraventricular Hypothalamic Nucleus
Neurogenesis
Genetic Promoter Regions
Energy Metabolism
Drosophila
Weight Gain
Transcription Factors
Central Nervous System
Chromosomes
Body Weight
Pharmacology

ASJC Scopus subject areas

  • Genetics

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Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. / Holder, J. Lloyd; Butte, Nancy F.; Zinn, Andrew R.

In: Human Molecular Genetics, Vol. 9, No. 1, 2000, p. 101-108.

Research output: Contribution to journalArticle

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