PMID- 10622252
OWN - NLM
STAT- MEDLINE
DCOM- 20000110
LR  - 20220408
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 402
IP  - 6764
DP  - 1999 Dec 23-30
TI  - Dominant negative mutations in human PPARgamma associated with severe insulin
      resistance, diabetes mellitus and hypertension.
PG  - 880-3
AB  - Thiazolidinediones are a new class of antidiabetic agent that improve insulin
      sensitivity and reduce plasma glucose and blood pressure in subjects with type 2 
      diabetes. Although these agents can bind and activate an orphan nuclear receptor,
      peroxisome proliferator-activated receptor gamma (PPARgamma), there is no direct 
      evidence to conclusively implicate this receptor in the regulation of mammalian
      glucose homeostasis. Here we report two different heterozygous mutations in the
      ligand-binding domain of PPARgamma in three subjects with severe insulin
      resistance. In the PPARgamma crystal structure, the mutations destabilize helix
      12 which mediates transactivation. Consistent with this, both receptor mutants
      are markedly transcriptionally impaired and, moreover, are able to inhibit the
      action of coexpressed wild-type PPARgamma in a dominant negative manner. In
      addition to insulin resistance, all three subjects developed type 2 diabetes
      mellitus and hypertension at an unusually early age. Our findings represent the
      first germline loss-of-function mutations in PPARgamma and provide compelling
      genetic evidence that this receptor is important in the control of insulin
      sensitivity, glucose homeostasis and blood pressure in man.
FAU - Barroso, I
AU  - Barroso I
AD  - Incyte Europe Ltd, Cambridge, UK.
FAU - Gurnell, M
AU  - Gurnell M
FAU - Crowley, V E
AU  - Crowley VE
FAU - Agostini, M
AU  - Agostini M
FAU - Schwabe, J W
AU  - Schwabe JW
FAU - Soos, M A
AU  - Soos MA
FAU - Maslen, G L
AU  - Maslen GL
FAU - Williams, T D
AU  - Williams TD
FAU - Lewis, H
AU  - Lewis H
FAU - Schafer, A J
AU  - Schafer AJ
FAU - Chatterjee, V K
AU  - Chatterjee VK
FAU - O'Rahilly, S
AU  - O'Rahilly S
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Benzoxazoles)
RN  - 0 (Ligands)
RN  - 0 (Nicotinic Acids)
RN  - 0 (Phenylpropionates)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (SB 236636)
RN  - 0 (Tetrahydronaphthalenes)
RN  - 0 (Thiazoles)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Transcription Factors)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - UVU4X1103P (LG 100268)
SB  - IM
CIN - Nature. 1999 Dec 23-30;402(6764):860-1. PMID: 10622250
MH  - Adult
MH  - Animals
MH  - Benzoxazoles/metabolism
MH  - Binding Sites
MH  - Diabetes Mellitus, Type 2/complications/*etiology/genetics
MH  - Female
MH  - Genes, Dominant
MH  - Humans
MH  - Hypertension/complications/*etiology/genetics
MH  - *Insulin Resistance/genetics
MH  - Ligands
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Models, Molecular
MH  - *Mutation
MH  - Nicotinic Acids/metabolism
MH  - Phenylpropionates/metabolism
MH  - Protein Conformation
MH  - Receptors, Cytoplasmic and Nuclear/chemistry/genetics/*physiology
MH  - Receptors, Retinoic Acid/metabolism
MH  - Retinoid X Receptors
MH  - Rosiglitazone
MH  - Tetrahydronaphthalenes/metabolism
MH  - Thiazoles/metabolism
MH  - *Thiazolidinediones
MH  - Transcription Factors/chemistry/genetics/metabolism/*physiology
EDAT- 2000/01/06 09:00
MHDA- 2001/03/23 10:01
CRDT- 2000/01/06 09:00
PHST- 2000/01/06 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 2000/01/06 09:00 [entrez]
AID - 10.1038/47254 [doi]
PST - ppublish
SO  - Nature. 1999 Dec 23-30;402(6764):880-3. doi: 10.1038/47254.