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

Studies of mice and humans have revealed a number of genes that when mutate d 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 trans location breakpoints. The translocation does not appear to affect any trans cription unit on 1p, but it disrupts the SIM1 gene on 6q, SIM1 encodes a hu man homolog of Drosophila Sim (SingIe-minded), a transcription factor invol ved in midline neurogenesis, and is a prototypical member of the bHLH-PAS ( basic helix-loop-helix + period, aryl hydrocarbon receptor, Singleminded) g ene family. Our subject's trans- location separates the 5' promoter region and bHLH domain from the 3' PAS and putative transcriptional regulation dom ains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expr essed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hy pothalamus, Previous neuroanatomical and pharmacological studies have impli cated the PVN in the regulation of body weight: PVN neurons express the mel anocortin 4 receptor and appear to be physiological targets of alpha-melano cyte-stimulating hormone, which inhibits food intake. We hypothesize that h aploinsufficiency of SIM1, possibly acting upstream or downstream of the me lanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.