Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.
PPARgamma is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARgamma in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARgamma coactivators and inhibit coexpressed wild-type receptor. Expression of PPARgamma target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARgamma action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.
Agostini
Maura
M
Department of Medicine, University of Cambridge, United Kingdom.
Schoenmakers
Erik
E
Mitchell
Catherine
C
Szatmari
Istvan
I
Savage
David
D
Smith
Aaron
A
Rajanayagam
Odelia
O
Semple
Robert
R
Luan
Jian'an
J
Bath
Louise
L
Zalin
Anthony
A
Labib
Mourad
M
Kumar
Sudhesh
S
Simpson
Helen
H
Blom
Dirk
D
Marais
David
D
Schwabe
John
J
Barroso
Inês
I
Trembath
Richard
R
Wareham
Nicholas
N
Nagy
Laszlo
L
Gurnell
Mark
M
O'Rahilly
Stephen
S
Chatterjee
Krishna
K
D004247:DNA / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D018076:DNA, Complementary; D047495:PPAR gamma; D004247:DNA