title: Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance.
abstract: 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.
authors.affiliation: Department of Medicine, University of Cambridge, United Kingdom.
authors.forename: Maura
authors.initials: M
authors.lastname: Agostini
authors.forename: Erik
authors.initials: E
authors.lastname: Schoenmakers
authors.forename: Catherine
authors.initials: C
authors.lastname: Mitchell
authors.forename: Istvan
authors.initials: I
authors.lastname: Szatmari
authors.forename: David
authors.initials: D
authors.lastname: Savage
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.forename: Odelia
authors.initials: O
authors.lastname: Rajanayagam
authors.forename: Robert
authors.initials: R
authors.lastname: Semple
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Louise
authors.initials: L
authors.lastname: Bath
authors.forename: Anthony
authors.initials: A
authors.lastname: Zalin
authors.forename: Mourad
authors.initials: M
authors.lastname: Labib
authors.forename: Sudhesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Helen
authors.initials: H
authors.lastname: Simpson
authors.forename: Dirk
authors.initials: D
authors.lastname: Blom
authors.forename: David
authors.initials: D
authors.lastname: Marais
authors.forename: John
authors.initials: J
authors.lastname: Schwabe
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Richard
authors.initials: R
authors.lastname: Trembath
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wareham
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
authors.forename: Mark
authors.initials: M
authors.lastname: Gurnell
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
mesh_terms: 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
chemical_list: D018076:DNA, Complementary; D047495:PPAR gamma; D004247:DNA