Peroxisome Proliferator-Activated Receptor-γ C190S Mutation Causes Partial Lipodystrophy

Lüdtke, Angelika; Buettner, Janine; Wu, Wei; Muchir, Antoine; Schroeter, Andreas; Zinn‐Justin, Sophie; Spuler, Simone; Schmidt, Hartmut; Worman, Howard J.

doi:10.1210/jc.2005-2624

Cited by 40 publications

(30 citation statements)

References 43 publications

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“…В 2007 г. Ludtke A. и соавт. [15] обнаружили еще одну гетерозиготную мутацию PPARG (C190S) у 3 пациентов в одной семье с парциальной липодистрофией. Мута-ция была расположена в ДНК-связывающей области, и мутантный белок обладал значительно меньшей спо-собностью к активации гена-репортера, чем дикий типа PPAR-гамма, даже при назначении росиглитазона.…”

Section: Discussionunclassified

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

et al. 2015

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Section: Discussionunclassified

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

et al. 2015

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“…In the same region of the DBD, several other human natural PPARγ amino acid substitutions, leading to loss-of-function or dominant-negative effects, have been reported resulting in FPLD3 with severe hypertension. [35][36][37] Leucine 339 is located in helix 3 close to other residues (S317, V318, K329, K347) interacting with helix 12 and involved in the stabilization of corepressor complexes. 40 Other naturally occurring PPARG mutations leading to LBD truncation, either acting via a dominant-negative or a haploinsufficiency mechanism, were responsible for typical FPLD3.…”

Section: Discussionmentioning

confidence: 99%

“…In this highly conserved region of the DBD (residues 139-192), 5 missense mutations (C142R, Y151C, C159Y, C190S, and C190W) have been associated with FPLD3 with severe hypertension. [35][36][37] Leucine 339 is conserved among PPARγ species and in PPARα and δ ( Figure 1A). The nonsense L339X mutation predicted a protein truncation within the central part of the LBD, as described in other natural FPLD3-linked PPARG mutations, that is, the dominant-negative Fs343X and R385X mutations that alter PPAR/RXR dimerization 35 and the Y355X alteration, which acts via a haploinsufficiency mechanism.…”

Section: Identification Of 2 Novel Pparγ Mutationsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin–Angiotensin System

Auclair

Vigouroux

Boccara

et al. 2013

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Objective-Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular reninangiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ. Approach and Results-We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II-mediated mitogenactivated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes. Conclusions-Two

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“…FPLD Type 3: Mutations in the peroxisome proliferatoractivated receptor gamma (PPARG) gene can cause partial lipodystrophy with abdominal obesity [28] known as FPLD3 [29] ; people with FPLD3 may look very similar to FPLD2. Treatment with thiazolidinediones may be useful in people with PPARG gene mutations [30] and other cases of FPLD without identified gene mutations [31] .…”

Section: Familial Partial Lipodystrophies (Fpld)mentioning

confidence: 99%

Rare adipose disorders (RADs) masquerading as obesity

2012

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Rare adipose disorders (RADs) including multiple symmetric lipomatosis (MSL), lipedema and Dercum's disease (DD) may be misdiagnosed as obesity. Lifestyle changes, such as reduced caloric intake and increased physical activity are standard care for obesity. Although lifestyle changes and bariatric surgery work effectively for the obesity component of RADs, these treatments do not routinely reduce the abnormal subcutaneous adipose tissue (SAT) of RADs. RAD SAT likely results from the growth of a brown stem cell population with secondary lymphatic dysfunction in MSL, or by primary vascular and lymphatic dysfunction in lipedema and DD. People with RADs do not lose SAT from caloric limitation and increased energy expenditure alone. In order to improve recognition of RADs apart from obesity, the diagnostic criteria, histology and pathophysiology of RADs are presented and contrasted to familial partial lipodystrophies, acquired partial lipodystrophies and obesity with which they may be confused. Treatment recommendations focus on evidencebased data and include lymphatic decongestive therapy, medications and supplements that support loss of RAD SAT. Associated RAD conditions including depression, anxiety and pain will improve as healthcare providers learn to identify and adopt alternative treatment regimens for the abnormal SAT component of RADs. Effective dietary and exercise regimens are needed in RAD populations to improve quality of life and construct advanced treatment regimens for future generations.

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Peroxisome Proliferator-Activated Receptor-γ C190S Mutation Causes Partial Lipodystrophy

Abstract: Mutation of a zinc-binding amino acid of PPARgamma leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.

Cited by 40 publications

References 43 publications

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

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

Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin–Angiotensin System

Rare adipose disorders (RADs) masquerading as obesity

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