PMID- 10587584
OWN - NLM
STAT- MEDLINE
DCOM- 20000229
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 9
IP  - 1
DP  - 2000 Jan 1
TI  - Profound obesity associated with a balanced translocation that disrupts the SIM1 
      gene.
PG  - 101-8
AB  - 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 (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.
FAU - Holder, J L Jr
AU  - Holder JL Jr
AD  - Eugene McDermott Center for Human Growth and Development and Department of
      Internal Medicine, The University of Texas Southwestern Medical School, Dallas,
      TX 75235, USA.
FAU - Butte, N F
AU  - Butte NF
FAU - Zinn, A R
AU  - Zinn AR
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Repressor Proteins)
RN  - 0 (SIM1 protein, human)
SB  - IM
MH  - Age of Onset
MH  - Basic Helix-Loop-Helix Transcription Factors
MH  - Child, Preschool
MH  - Chromosomes, Bacterial
MH  - *Chromosomes, Human, Pair 1
MH  - *Chromosomes, Human, Pair 6
MH  - Cloning, Molecular
MH  - Databases, Factual
MH  - Female
MH  - Helix-Loop-Helix Motifs
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Infant
MH  - Infant, Newborn
MH  - Mutation
MH  - Obesity/*genetics
MH  - Pregnancy
MH  - Repressor Proteins/*genetics
MH  - *Translocation, Genetic
EDAT- 1999/12/10 09:00
MHDA- 2000/03/04 09:00
CRDT- 1999/12/10 09:00
PHST- 1999/12/10 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 1999/12/10 09:00 [entrez]
AID - ddd012 [pii]
AID - 10.1093/hmg/9.1.101 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2000 Jan 1;9(1):101-8. doi: 10.1093/hmg/9.1.101.