Familial Partial Lipodystrophy Phenotype Resulting from a Single-Base Mutation in Deoxyribonucleic Acid-Binding Domain of Peroxisome Proliferator-Activated Receptor-γ

Abstract

The R194W mutation in PPARG disrupts its DNA binding activity and through haploinsufficiency leads to clinical manifestation of FPLD3 and the associated metabolic disturbances.

Adipogenesis

“…Of note, PPARg heterozygote mice show enhanced insulin sensitivity (Miles et al 2000), suggesting the amount of protein present is highly important. The importance of PPARg in human adipose tissue has also been established, and subjects with mutations in the PPARg gene can develop severe insulin resistance and lipodystrophy (Barroso et al 1999;Doney et al 2004;Monajemi et al 2007). Taken together, these studies show the requirement for PPARg in adipocyte differentiation and whole-body insulin sensitivity.…”

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

“…FPLD3 (MIM 604367) results from any of more than a dozen heterozygous mutations in the PPARG gene encoding peroxisome proliferator-activated receptor g (PPARg; MIM 601487) (43)(44)(45)(46)(47)(48)(49)(50)(51). The PPARG mutations implicated in FPLD3 are shown in Fig.…”

“…Careful cellular assays indicate that seven PPARg mutations (C114R, C131Y, C162W, FS315X, R357X, P467L, and V290M) act via a dominant negative mechanism (44,51), whereas six PPARg mutations (214A.G, F388L, E138fsDAATG, Y355X, R194W, and R425C) act through haploinsufficiency (45)(46)(47)(48)(49)(50) (Fig. 2).…”

“…The severity of adipose tissue loss and metabolic disturbances appears to be similar among individuals with dominant negative and haploinsufficiency mutations. All FPLD3 patients with PPARG haploinsufficiency mutations were ascertained based upon a clinical diagnosis of lipodystrophy (45)(46)(47)(48)(49)(50). Thus, virtually every patient with a PPARG mutation has had partial lipodystrophy as a core phenotype.…”

Development of metabolic syndrome at a young age as a manifestation of familial partial lipodystrophy type 3 (PPARG mutation): the first description of its clinical case in Russia

“…Для СПЛД 3 типа характерно более мягкое клиническое течение и меньшая выраженность патологического перераспре-деления подкожно-жировой клетчатки, при сохраня-ющихся проявлениях МС [3]. Таким образом, данный вариант СПЛД требует особого внимания клиницистов для своевременного установления диагноза в случаях со-четания выраженных метаболических нарушений в мо-лодом возрасте, что способствует более эффективному лечению пациентов и проведению медико-генетиче-ского консультирования их семей [4]. , дислипидемия (тригли-цериды 10,35 ммоль/л, общий холестерин 7,00 ммоль/л, холестерин ЛПОНП 2,07 ммоль/л), гиперурикемия (мо-чевая кислота 450,9 мкмоль/л при норме до 416,5).…”