Lamin A/C gene -: Sex-determined expression of mutations in dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy
Lamin A/C gene -: Sex-determined expression of mutations in dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy
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DOI：
10.2337/diabetes.49.11.1958
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发表时间：
2000-11-01
期刊：
影响因子：
7.7
通讯作者：
Capeau, J
中科院分区：
文献类型：
--
作者：
Vigouroux, C;Magré, J;Capeau, J
错义突变的核纤层蛋白A/C基因，LMNA，最近已确定在Dunnigan型家族性部分脂肪营养不良（FPLD），这属于一个异质性组的罕见疾病影响脂肪组织分布和代谢。在这项研究中，我们对患有FPLD或其他形式的脂肪营养不良的患者的LMNA编码区进行了测序。我们在具有不同临床表现的FPLD患者（6个家族和1个个体）中发现了外显子8的两个杂合突变R482 W和R482 Q。此外，我们发现了一个新的杂合突变（R584 H）在外显子11，编码核纤层蛋白A亚型，在典型的FPLD患者。FPLD患者的临床和生化研究显示，表型的表达和严重程度明显依赖于性别，女性患者受到更明显的影响。在患有全身性脂肪萎缩的受试者中，无论是先天性（13例受试者）还是获得性（14例受试者），或者Barraquer-Simon综合征（2例受试者），整个LMNA编码序列均正常。虽然FPLD突变主要定位于LMNA的外显子8中，但在密码子584处发现的新突变以及最近描述的R582 H杂合取代证实了核纤层蛋白A同种型特异性的C-末端区域是FPLD突变的第二易感区域。
Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.