Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
J Clin Endocrinol Metab. 2011 May;96(5):E856-62. doi: 10.1210/jc.2010-2234. Epub 2011 Feb 23.
Mutations in LMNA, encoding A-type lamins, lead to multiple laminopathies, including lipodystrophies, progeroid syndromes, and cardiomyopathies. Alterations in the prelamin-A posttranslational maturation, resulting in accumulation of farnesylated isoforms, cause human progeroid syndromes. Accumulation of mutant nonfarnesylated prelamin-A leads to cardiomyopathy or progeria in mice, but no data have been provided in humans. OBJECTIVE, DESIGN, SETTING, AND PATIENTS: We searched for LMNA mutations in seven women originating from Reunion Island who were referred for a severe lipodystrophic syndrome. Clinical, molecular, genealogical, and cellular studies were performed in probands and relatives.
The seven probands showed a severe partial lipodystrophic syndrome with diabetes and/or acanthosis nigricans, liver steatosis, hypertriglyceridemia, and low serum leptin and adiponectin levels. Three probands also had severe cardiac rhythm and conduction disturbances. We identified in all probands a homozygous LMNA p.T655fsX49 mutation leading to expression of a mutated prelamin-A with 48 aberrant C-terminal amino acids, preventing its physiological posttranslational farnesylation and maturation. Genealogical and haplotype analyses were consistent with a founder mutation transmitted from a common ancestor in the 17th century. In probands' cultured fibroblasts, mutated prelamin-A was associated with typical laminopathic nuclear dysmorphies, increased oxidative stress, and premature senescence. Heterozygous relatives were asymptomatic or partially affected, in favor of a codominant transmission of the disease with incomplete penetrance in heterozygotes.
We reveal that a homozygous mutation of prelamin-A preventing its farnesylation leads to a severe lipodystrophic laminopathy in humans, which can be associated with cardiac conduction disturbances, stressing the pathogenicity of nonfarnesylated prelamin-A in human laminopathies.
编码 A 型核纤层蛋白的 LMNA 基因突变可导致多种核纤层病，包括脂肪营养不良、早老综合征和心肌病。前层粘连蛋白 A 的翻译后成熟改变，导致法尼基化同工型的积累，引起人类早老综合征。突变的非法尼基化前层粘连蛋白 A 的积累导致小鼠的心肌病或早衰，但在人类中没有提供数据。
目的、设计、设置和患者：我们在来自留尼汪岛的 7 名因严重脂肪营养不良综合征而就诊的女性中寻找 LMNA 突变。对先证者及其亲属进行了临床、分子、遗传和细胞研究。
7 名先证者表现出严重的部分脂肪营养不良综合征，伴有糖尿病和/或黑棘皮病、肝脂肪变性、高三酰甘油血症、血清瘦素和脂联素水平低。3 名先证者也有严重的心律失常和传导障碍。我们在所有先证者中均发现了一个纯合的 LMNA p.T655fsX49 突变，导致表达一种带有 48 个异常 C 末端氨基酸的突变前层粘连蛋白 A，从而阻止其生理翻译后法尼基化和成熟。遗传和单倍型分析与 17 世纪从共同祖先传播的启动子突变一致。在先证者培养的成纤维细胞中，突变的前层粘连蛋白 A 与典型的核纤层病核畸形、氧化应激增加和过早衰老有关。杂合亲属无症状或部分受累，有利于疾病的共显性遗传，杂合子不完全外显。
我们揭示了一种阻止前层粘连蛋白 A 法尼基化的前层粘连蛋白 A 纯合突变可导致人类严重的脂肪营养不良性核纤层病，可伴有心脏传导障碍，强调了非法尼基化前层粘连蛋白 A 在人类核纤层病中的致病性。
