BES2003 Oral Communications Cardiovascular Endocrinology (8 abstracts)
A novel PPAR gamma mutation (R357X), associated with partial lipodystrophy, helps define the phenotype of the human PPAR gamma ligand resistance (PLR) syndrome
M Agostini 1 , O Rajanayagam 1 , AG Smith 1 , DB Savage 1,2 , M Labib 3 , AM Zalin 3 , S O'Rahilly 1,2 , RC Trembath 4 , VKK Chatterjee 1 & M Gurnell 1
1Department of Medicine, University of Cambridge, Cambridge, UK; 2Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK; 3Department of Medicine, Wordsley Hospital, Wordsley, UK; 4Department of Medicine, University of Leicester, Leicester, UK.
Previously we reported two loss-of-function dominant negative mutations (P467L, V290M) in human peroxisome proliferator-activated receptor gamma (PPARg) in three individuals with severe insulin resistance, early onset type 2 diabetes mellitus (T2DM) and hypertension. Subsequent detailed clinical and radiological evaluation of these subjects has revealed that each exhibits a stereotyped pattern of partial lipodystrophy affecting the limbs and buttocks. Recently a female with partial lipodystrophy, T2DM and hypertension, was shown to harbour a mutation in PPARg (R397C) (JCEM 2002, 87(1):408-411), and our functional studies indicate that this mutant receptor is also transcriptionally impaired, with dominant negative activity.
Accordingly, we have screened a cohort of subjects with partial lipodystrophy, and now report the identification of a fourth novel loss-of-function mutation within PPARg (R357X), which truncates the receptor after helix 6 within the ligand-binding domain, resulting in severe transcriptional impairment. MRI and detailed body composition studies confirm the distinctive pattern of partial lipodystrophy observed in earlier subjects. In addition, the affected female also exhibits several clinical features, including insulin resistance with early onset T2DM and hypertension, dyslipidaemia (high triglycerides, low HDL cholesterol), hepatic steatosis, polycystic ovarian syndrome and pre-eclampsia, which we now suggest to be typical of the human PPARg ligand resistance (PLR) syndrome.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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