A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations
A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations
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DOI：
10.2337/db17-1236
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发表时间：
2018-06-01
期刊：
影响因子：
7.7
通讯作者：
Savage, David B.
中科院分区：
文献类型：
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作者：
Agostini, Maura;Schoenmakers, Erik;Savage, David B.
PPARG功能缺失突变导致家族性部分脂肪营养不良3型（FPLD 3）和许多患者的严重代谢疾病。PPARG中的错义突变存在于大约1/500的人中。虽然突变通常被二进制分类为良性或有害的，所有的错义PPARG变体的前瞻性功能分类表明，它们的影响是分级的。此外，在测试具有原型内源性（例如，前列腺素J2 [PGJ 2]）和合成配体（噻唑烷二酮类，酪氨酸激动剂），我们观察到合成激动剂选择性地拯救一些过氧化物酶体增殖物激活受体γ（PPAR γ）突变体的功能。我们报告了携带两种这样的PPAR γ突变（R308 P和A261 E）的FPLD 3患者。这两种PPAR γ突变体表现出可忽略的组成或PGJ 2诱导的转录活性，但在体外很容易响应合成激动剂，结构建模提供了这种差异配体依赖性反应的基础。与这一发现一致，吡格列酮治疗R308 P突变型PPAR γ患者后观察到显著的临床改善。一名A261 E突变型PPAR γ的患者也对罗格列酮产生了有益的反应，尽管心肌病排除了长期使用噻唑烷二酮。这些观察结果表明，详细的结构和功能分类可用于告知PPARG突变患者的治疗决策。
Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missensemutations in PPARG are present in similar to 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-gamma (PPAR gamma) mutants. We report on patients with FPLD3 who harbor two such PPAR gamma mutations (R308P and A261E). Both PPAR gamma 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 PPAR gamma. A patient with A261E mutant PPAR gamma 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.