New metabolic phenotypes in laminopathies:: LMNA mutations in patients with severe metabolic syndrome
New metabolic phenotypes in laminopathies:: LMNA mutations in patients with severe metabolic syndrome
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DOI：
10.1210/jc.2007-0654
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发表时间：
2007-12-01
影响因子：
5.8
通讯作者：
Vigouroux, Corinne
中科院分区：
文献类型：
--
作者：
Decaudain, Aurélie;Vantyghem, Marie-Christine;Vigouroux, Corinne
背景：LMNA 基因突变导致多种核纤层蛋白病，包括脂肪营养不良，具有复杂的基因型/表型关系。 目的、设计、背景和患者：对 277 名不相关的成人进行脂肪营养不良和/或胰岛素抵抗研究，对 LMNA 编码区进行测序，发现 17 名患者在典型邓尼根家族性部分脂肪营养不良和胰岛素抵抗中观察到密码子 482 发生替换。 10名患有其他突变的患者。我们在这里报告了非密码子 482 突变患者的表型，并将其与 11 名密码子 482 突变患者的表型进行了比较。我们还研究了 7 名患者的皮肤成纤维细胞或淋巴细胞。结果：在此处研究的 9 名患者中发现的 LMNA 突变影响了三个蛋白质结构域。其中八个是新颖的。 10名非密码子482相关突变的患者符合国际糖尿病联盟代谢综合征的诊断标准。他们中的大多数缺乏邓尼根家族性部分脂肪营养不良症中观察到的典型脂肪萎缩。然而，密码子 482 和非密码子 482 相关突变患者的胰岛素抵抗、葡萄糖耐量改变和高甘油三酯血症的严重程度以及细胞核的改变相似。 9 名非密码子 482 LMNA 突变患者出现小腿肥大、肌痛和肌肉痉挛或无力，两名非密码子 482 LMNA 突变患者出现心脏传导障碍。结论：我们在此描述了与非密码子 482 LMNA 突变相关的代谢性核纤层病变的新表型，其特征是，在没有明显的临床脂肪萎缩的情况下，出现严重的代谢改变和频繁的肌肉体征（肌肉肥大、肌痛或无力）。双能 X 射线吸收测定法和/或腹部和大腿横截面成像可以通过揭示亚临床脂肪营养不良来帮助诊断。代谢性核纤层蛋白病的患病率和病理生理学需要进一步研究。
Context: Mutations in the LMNA gene are responsible for several laminopathies, including lipodystrophies, with complex genotype/phenotype relationships.Objective, Design, Setting, and Patients: Sequencing of the LMNA coding regions in 277 unrelated adults investigated for lipodystrophy and/or insulin resistance revealed 17 patients with substitutions at codon 482 observed in typical Dunnigan's familial partial lipodystrophy and 10 patients with other mutations. We report here the phenotypes of the patients with non-codon 482 mutations and compare them with those of 11 patients with codon 482 mutations. We also studied skin fibroblasts or lymphocytes from seven patients.Results: LMNA mutations found in nine patients studied here affected the three protein domains. Eight of them were novel. The 10 patients with non-codon 482-associated mutations fulfilled the International Diabetes Federation diagnosis criteria for metabolic syndrome. Most of them lacked the typical lipoatrophy observed in Dunnigan's familial partial lipodystrophy. However, the severity of insulin resistance, altered glucose tolerance, and hypertriglyceridemia and the alterations of cell nuclei were similar in patients with codon 482- and non-codon 482- associated mutations. Calf hypertrophy, myalgia, and muscle cramps or weakness were present in nine patients and cardiac conduction disturbances in two patients with non-codon 482 LMNA mutations.Conclusions: We describe here new phenotypes of metabolic laminopathy associated with non-codon 482 LMNA mutations and characterized, in the absence of obvious clinical lipoatrophy, by severe metabolic alterations and frequent muscle signs ( muscular hypertrophy, myalgias, or weakness). Dual-energy x-ray absorptiometry and/or cross-sectional abdominal and thigh imaging can help diagnosis by revealing subclinical lipodystrophy. The prevalence and pathophysiology of metabolic laminopathies need to be studied further.