A pharmacogenetic approach to the treatment of patients with PPARG mutations

Maura Agostini; Erik Schoenmakers; Junaid Beig; Louise Fairall; Istvan Szatmari; Odelia Rajanayagam; Frederick Muskett; Claire Adams; David Marais; Stephen O'Rahilly; Robert Semple; Laszlo Nagy; Amit Majithia; John Schwabe; Dirk J Blom; Rinki Murphy; Krishna Chatterjee; David B Savage

A pharmacogenetic approach to the treatment of patients with PPARG mutations

Maura Agostini, Erik Schoenmakers, Junaid Beig, Louise Fairall, Istvan Szatmari, Odelia Rajanayagam, Frederick Muskett, Claire Adams, David Marais, Stephen O'Rahilly, Robert Semple, Laszlo Nagy, Amit Majithia, John Schwabe, Dirk J Blom, Rinki Murphy, Krishna Chatterjee, David B Savage

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Abstract / Description of output

Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ~1:500 people. Whilst 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 PPARg mutants. Here, we report FPLD3 patients, harbouring two such PPARg mutations (R308P, A261E). Both PPARg mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modelling providing a basis for such differential ligand-dependent
responsiveness. Concordant with this, dramatic clinical improvement was seen following pioglitazone treatment of the patient with R308P mutant PPARg. A patient with A261E mutant PPARg also responded beneficially to rosiglitazone, though 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.

Original language	English
Journal	Diabetes
Publication status	Published - 5 Apr 2018

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This is the authors accepted manuscript as accepted by Diabetes n 27th March 2018
Accepted author manuscript, 2.34 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

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@article{daeaa380ec8f4ded95f4787cd77bf303,

title = "A pharmacogenetic approach to the treatment of patients with PPARG mutations",

abstract = "Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ~1:500 people. Whilst mutations are often binarily classified as {\textquoteleft}benign{\textquoteright} or {\textquoteleft}deleterious{\textquoteright}, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic {\textquoteleft}endogenous{\textquoteright} (e.g. prostaglandin J2(PGJ2)) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some PPARg mutants. Here, we report FPLD3 patients, harbouring two such PPARg mutations (R308P, A261E). Both PPARg mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modelling providing a basis for such differential ligand-dependentresponsiveness. Concordant with this, dramatic clinical improvement was seen following pioglitazone treatment of the patient with R308P mutant PPARg. A patient with A261E mutant PPARg also responded beneficially to rosiglitazone, though 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.",

author = "Maura Agostini and Erik Schoenmakers and Junaid Beig and Louise Fairall and Istvan Szatmari and Odelia Rajanayagam and Frederick Muskett and Claire Adams and David Marais and Stephen O'Rahilly and Robert Semple and Laszlo Nagy and Amit Majithia and John Schwabe and Blom, {Dirk J} and Rinki Murphy and Krishna Chatterjee and Savage, {David B}",

note = "Acknowledgements We are very grateful to the patients for their willingness to participate in these studies. D.B.S. and K.C and J.W.R.S are supported by the Wellcome Trust (grants WT107064, WT095564 and WT100237), the MRC Metabolic Disease Unit, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Rare Disease Translational Research Collaboration. J.W.R.S. is a Royal Society Wolfson Research Merit Award Holder. Dr. David Savage is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis. Duality of Interest. The authors report no potential conflicts of interest relevant to this article. Author contributions. M.A., E.S., undertook functional studies of the mutants, analysed data and wrote parts of the manuscript. J.B. and R.M., characterised and treated proband 1, and wrote parts of the manuscript. O.R. performed sequencing studies, identified the PPARG mutations and reviewed the manuscript. C.A., co-ordinated studies and reviewed the manuscript. I.S., S.O{\textquoteright}R., R.K.S., L.N., A.R.M. analysed data and reviewed the manuscript. E.S., L.F., F.W.M., J.W.R.S., undertook structural modelling of mutations, circular dichroism and NMR studies and reviewed the manuscript. A.D.M. and D.J.B. characterised probands 2 and 3, analysed data and wrote parts of the manuscript. R.M., K.C. and D.B.S. planned studies, analysed data and wrote the manuscript.",

year = "2018",

month = apr,

day = "5",

language = "English",

journal = "Diabetes",

issn = "0012-1797",

publisher = "AMER DIABETES ASSOC",

}

TY - JOUR

T1 - A pharmacogenetic approach to the treatment of patients with PPARG mutations

AU - Agostini, Maura

AU - Schoenmakers, Erik

AU - Beig, Junaid

AU - Fairall, Louise

AU - Szatmari, Istvan

AU - Rajanayagam, Odelia

AU - Muskett, Frederick

AU - Adams, Claire

AU - Marais, David

AU - O'Rahilly, Stephen

AU - Semple, Robert

AU - Nagy, Laszlo

AU - Majithia, Amit

AU - Schwabe, John

AU - Blom, Dirk J

AU - Murphy, Rinki

AU - Chatterjee, Krishna

AU - Savage, David B

N1 - Acknowledgements We are very grateful to the patients for their willingness to participate in these studies. D.B.S. and K.C and J.W.R.S are supported by the Wellcome Trust (grants WT107064, WT095564 and WT100237), the MRC Metabolic Disease Unit, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Rare Disease Translational Research Collaboration. J.W.R.S. is a Royal Society Wolfson Research Merit Award Holder. Dr. David Savage is the guarantor of this work and takes responsibility for the integrity of the data and the accuracy of the data analysis. Duality of Interest. The authors report no potential conflicts of interest relevant to this article. Author contributions. M.A., E.S., undertook functional studies of the mutants, analysed data and wrote parts of the manuscript. J.B. and R.M., characterised and treated proband 1, and wrote parts of the manuscript. O.R. performed sequencing studies, identified the PPARG mutations and reviewed the manuscript. C.A., co-ordinated studies and reviewed the manuscript. I.S., S.O’R., R.K.S., L.N., A.R.M. analysed data and reviewed the manuscript. E.S., L.F., F.W.M., J.W.R.S., undertook structural modelling of mutations, circular dichroism and NMR studies and reviewed the manuscript. A.D.M. and D.J.B. characterised probands 2 and 3, analysed data and wrote parts of the manuscript. R.M., K.C. and D.B.S. planned studies, analysed data and wrote the manuscript.

PY - 2018/4/5

Y1 - 2018/4/5

N2 - Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ~1:500 people. Whilst 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 PPARg mutants. Here, we report FPLD3 patients, harbouring two such PPARg mutations (R308P, A261E). Both PPARg mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modelling providing a basis for such differential ligand-dependentresponsiveness. Concordant with this, dramatic clinical improvement was seen following pioglitazone treatment of the patient with R308P mutant PPARg. A patient with A261E mutant PPARg also responded beneficially to rosiglitazone, though 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.

AB - Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ~1:500 people. Whilst 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 PPARg mutants. Here, we report FPLD3 patients, harbouring two such PPARg mutations (R308P, A261E). Both PPARg mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modelling providing a basis for such differential ligand-dependentresponsiveness. Concordant with this, dramatic clinical improvement was seen following pioglitazone treatment of the patient with R308P mutant PPARg. A patient with A261E mutant PPARg also responded beneficially to rosiglitazone, though 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.

M3 - Article

SN - 0012-1797

JO - Diabetes

JF - Diabetes

ER -

A pharmacogenetic approach to the treatment of patients with PPARG mutations

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