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001-es BibID:	BIBFORM074271
035-os BibID:	(WoS)000438781600007 (Scopus)85047721348
Első szerző:	Agostini, Maura
Cím:	A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations / Maura Agostini, Erik Schoenmakers, Junaid Beig, Louise Fairall, Istvan Szatmari, Odelia Rajanayagam, Frederick W. Muskett, Claire Adams, A. David Marais, Stephen O'Rahilly, Robert K. Semple, Laszlo Nagy, Amit R. Majithia, John W. R. Schwabe, Dirk J. Blom, Rinki Murphy, Krishna Chatterjee, David B. Savage
Dátum:	2018
ISSN:	0012-1797
Megjegyzések:	Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ?1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Diabetes. - 67 : 6 (2018), p. 1086-1092. -
További szerzők:	Schoenmakers, Erik Beig, Junaid Fairall, Louise Szatmári István (1971-) (biológus) Rajanayagam, Odelia Muskett, Frederick W. Adams, Claire Marais, A. David O'Rahilly, Stephen Semple, Robert K. Nagy László (1966-) (molekuláris sejtbiológus, biokémikus) Majithia, Amit R. Schwabe, John W. R. Blom, Dirk J. Murphy, Rinki Chatterjee, Krishna Savage, David B.
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM037946
Első szerző:	Agostini, Maura
Cím:	Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance / Agostini M., Schoenmakers E., Mitchell C., Szatmari I., Savage D., Smith A., Rajanayagam O., Semple R., Luan J., Bath L., Zalin A., Labib M., Kumar S., Simpson H., Blom D., Marais D., Schwabe J., Barroso I., Trembath R., Wareham N., Nagy L., Gurnell M., O'Rahilly S., Chatterjee K.
Dátum:	2006
ISSN:	1550-4131
Megjegyzések:	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.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Cell Metabolism. - 4 : 4 (2006), p. 303-311. -
További szerzők:	Schoenmakers, Erik Mitchell, Catherine Szatmári István (1971-) (biológus) Savage, David Smith, Aaron Rajanayagam, Odelia Semple, Robert Luan, Jian'an Bath, Louise Zalin, Anthony Labib, Mourad Kumar, Sudhesh Simpson, Helen Blom, Dirk Marais, David Schwabe, John Barroso, Inês Trembath, Richard Wareham, Nicholas Nagy László (1966-) (molekuláris sejtbiológus, biokémikus) Gurnell, Mark O'Rahilly, Stephen Chatterjee, Krishna
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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