PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy
PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy
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DOI：
10.2337/diabetes.51.12.3586
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发表时间：
2002-12-01
期刊：
影响因子：
7.7
通讯作者：
Leff, T
中科院分区：
文献类型：
--
作者：
Hegele, RA;Cao, HN;Leff, T
由编码核纤层蛋白 A/C 的突变 LMNA 引起的常染色体显性家族性部分脂肪营养不良 (FPLD) 的特点是脂肪组织重新分配以及多种代谢紊乱，包括胰岛素抵抗和血脂异常。有新出现的证据表明有些罕见。由 PPARG 编码的过氧化物酶体增殖物激活受体-γ (PPAR-γ) 突变可能与人类脂肪营养不良有关。我们报告了一个基于部分脂肪营养不良而确定的三代加拿大亲属，具有正常的 LMNA 基因序列。候选基因测序显示，所有四名受影响受试者的外显子 5 中 PPARG 核苷酸 1164 处存在新的 T-->A 突变，该突变预测密码子 388 处的苯丙氨酸将被亮氨酸 (F388L) 取代。正常家庭成员和正常无关受试者中不存在突变 I，并且改变了预测的 PPAR-γ 配体结合口袋的螺旋 8 内的高度保守残基。突变受体显着降低了基础转录活性并削弱了合成配体的刺激。 PPARG 反式激活缺陷突变的种系传递表明常染色体显性部分脂肪营养不良具有遗传异质性。我们的研究结果与突变 PPARG 可能是部分脂肪营养不良表型的基础的观点一致。
Autosomal dominant familial partial lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare. mutations in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), encoded by PPARG, might be associated with human lipodystrophy. We report A three-generation Canadian kindred ascertained based upon partial lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T-->A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation I was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-gamma. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype.