Here's the NEJM abstract:
The New England Journal of Medicine -- October 1, 1998 -- Volume 339, Number 14
Obesity Associated with a Mutation in a Genetic Regulator of
Adipocyte Differentiation
Michael Ristow, Dirk Muller-Wieland, Andreas Pfeiffer, Wilhelm Krone, C. Ronald Kahn
Abstract
Background. There is increasing evidence of genetic factors leading to obesity, but the exact genes involved have
not been defined. Peroxisome-proliferator-activated receptor (gamma)2 (PPAR(gamma)2) is a transcription
factor that has a key role in adipocyte differentiation, and therefore mutations of the gene for this factor might
predispose people to obesity.
Methods. We studied 358 unrelated German subjects, including 121 obese subjects (defined as those with a
body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 29). We
evaluated these subjects for mutations in the gene for PPAR(gamma)2 at or near a site of serine phosphorylation
at position 114 that negatively regulates the transcriptional activity of the protein, using a
polymerase-chain-reaction-based assay coupled with specific endonuclease digestion. The activity of the mutation
identified was analyzed by retroviral transfection and overexpression in murine fibroblasts.
Results. Four of the 121 obese subjects had a missense mutation in the gene for PPAR(gamma)2 that resulted in
the conversion of proline to glutamine at position 115, as compared with none of the 237 subjects of normal
weight (P=0.01). All the subjects with the mutant allele were markedly obese, with body-mass-index values
ranging from 37.9 to 47.3, as compared with a mean of 33.6 in the other obese subjects. Overexpression of the
mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at
position 114 was defective, as well as to accelerated differentiation of the cells into adipocytes and greater cellular
accumulation of triglyceride than with the wild-type PPAR(gamma)2. These effects were similar to those of an in
vitro mutation created directly at the Ser114 phosphorylation site.
Conclusions. A Pro115Gln mutation in PPAR(gamma)2 accelerates the differentiation of adipocytes and may
cause obesity. (N Engl J Med 1998;339:953-9.)
Source Information
From the Joslin Diabetes Center and Harvard Medical School, Boston (M.R., C.R.K.); the Klinik II und
Poliklinik fur Innere Medizin, Universitat zu Koln, Cologne, Germany (M.R., D.M.-W., W.K.); and the
Medizinische Klinik und Poliklinik, Bergmannsheil, Ruhr-Universitat Bochum, Bochum, Germany (A.P.). Address
reprint requests to Dr. Kahn at the Joslin Diabetes Center, Research Division, Section on Cellular and Molecular
Physiology, 1 Joslin Pl., Boston, MA 02215.
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