Decaudain Aurélie, Vantyghem Marie-Christine, Guerci Bruno, Hécart Annie-Claude, Auclair Martine, Reznik Yves, Narbonne Hervé, Ducluzeau Pierre-Henri, Donadille Bruno, Lebbé Céleste, Béréziat Véronique, Capeau Jacqueline, Lascols Olivier, Vigouroux Corinne
INSERM U680, Paris, F-75012 France.
J Clin Endocrinol Metab. 2007 Dec;92(12):4835-44. doi: 10.1210/jc.2007-0654. Epub 2007 Aug 21.
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.
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.
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.
LMNA基因突变与多种核纤层蛋白病有关，包括脂肪营养不良，其基因型/表型关系复杂。目的、设计、研究地点和患者：对277名因脂肪营养不良和/或胰岛素抵抗接受调查的无亲缘关系的成年人进行LMNA编码区测序，发现17名患者在典型的邓尼根家族性部分脂肪营养不良中观察到密码子482处有替代，10名患者有其他突变。我们在此报告非密码子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。
在此研究的9名患者中发现的LMNA突变影响了三个蛋白质结构域。其中8个是新发现的。10名与非密码子482相关突变的患者符合国际糖尿病联盟代谢综合征诊断标准。他们中的大多数缺乏在邓尼根家族性部分脂肪营养不良中观察到的典型脂肪萎缩。然而，密码子482相关突变和非密码子482相关突变患者的胰岛素抵抗严重程度、糖耐量改变、高甘油三酯血症以及细胞核改变相似。9名非密码子482 LMNA突变患者出现小腿肥大、肌痛、肌肉痉挛或无力，2名患者出现心脏传导障碍。
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蛋白病的新表型，其特征是在无明显临床脂肪萎缩的情况下，有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线吸收法和/或腹部及大腿横断面成像可通过发现亚临床脂肪营养不良来辅助诊断。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。
