High prevalence of laminopathies among patients with metabolic syndrome
High prevalence of laminopathies among patients with metabolic syndrome
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DOI：
10.1093/hmg/ddr294
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发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Morange, Pierre-Emmanuel
中科院分区：
文献类型：
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作者：
Dutour, Anne;Roll, Patrice;Morange, Pierre-Emmanuel
体质性核纤层蛋白病，如邓尼根家族性部分脂肪营养不良，是由A型核纤层蛋白突变引起的严重疾病，与代谢综合征（MS）有几个共同特征。在这项研究中，我们假设MS在某些情况下可能是一种轻度的核纤层蛋白病，并使用在这些疾病中观察到的异常细胞核表型作为普通MS患者的初步筛选试验。在87名连续MS患者的淋巴母细胞样细胞中系统地搜索核形状和核纤层蛋白A核质分布异常。对编码A型核纤层蛋白或核纤层蛋白A成熟途径的酶的五个基因进行系统测序（LMNA、ZMPSTE 24、ICMT、FNTA和FNTB）。我们确定了10例MS患者表现为核形状异常和核纤层蛋白A/C分布紊乱。这些患者在临床上与无核异常的患者没有区别，除了他们更年轻，并且有更高的血肌酐和SGPT水平。其中三个携带LMNA或ZMPSTE 24的杂合突变，ZMPSTE 24是编码核纤层蛋白A加工酶之一的基因。所有这三种突变都是新的错义突变，预计会造成损害。来自携带ZMPSTE 24突变的患者的淋巴母细胞和皮肤成纤维细胞都显示出核纤层蛋白A前体的积累，表明核纤层蛋白A加工的改变，这一点得到了功能研究的证实。很大比例的MS患者表现出核纤层蛋白病，并建议在诊断此疾病时应进行核纤层蛋白A及其伴侣的系统研究。综合征
Constitutional laminopathies, such as the Dunnigan familial partial lipodystrophy, are severe diseases caused by mutations in A-type lamins and share several features with metabolic syndrome (MS). In this study, we hypothesized that MS may be, in some cases, a mild form of laminopathies and use the abnormal cell nucleus phenotype observed in these diseases as a primary screening test in patients suffering from common MS.Nuclear shape and lamin A nucleoplasmic distribution abnormalities were systematically searched in lymphoblastoid cells of 87 consecutive patients with MS. In parallel, five genes encoding either the A-type lamins or the enzymes of the lamin A maturation pathway were systematically sequenced (LMNA, ZMPSTE24, ICMT, FNTA and FNTB). We identified 10 MS patients presenting abnormal nuclear shape and disturbed lamin A/C nuclear distribution. These patients were not clinically different from those without nuclear abnormalities except that they were younger, and had higher triglyceridemia and SGPT levels. Three of them carry a heterozygous mutation in LMNA or in ZMPSTE24, a gene encoding one of the lamin A processing enzymes. All three mutations are novel missense mutations predicted to be damaging. Both lymphoblastoid cells and skin fibroblasts from the patient carrying the mutation in ZMPSTE24, showed accumulation of lamin A precursor, indicating an alteration of the lamin A processing, confirmed by functional study.Together, these results show for the first time, that a significant proportion of MS patients exhibits laminopathies and suggest that systematic investigation of lamin A and its partners should be performed at the diagnosis of this syndrome.