LMNA mutations in atypical Werner's syndrome
LMNA mutations in atypical Werner's syndrome
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DOI：
10.1016/s0140-6736(03)14069-x
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发表时间：
2003-08-09
期刊：
影响因子：
168.9
通讯作者：
Oshima, J
中科院分区：
文献类型：
--
作者：
Chen, LS;Lee, L;Oshima, J
研究背景Werner综合征是一种由WRN解旋酶基因突变引起的早幼粒综合征。由于这种相似性，我们对非典型Werner综合征(野生型WRN)患者的LMNA进行了测序。方法在我们的国际Werner综合征分子诊断登记中，有26例(20%)具有野生型WRN编码区，并根据分子标准将其归类为非典型Werner综合征。我们对这些个体的LMNA的所有外显子进行了测序。RT-PCR测序证实突变发生在mRNA水平。在一名检测到LMNA突变并有成纤维细胞可用的患者中，我们建立了核形态和亚核定位。在26名非典型Werner综合征患者中，我们发现了4名(15%)LMNA新的错义突变，特别是A57P、R133L(两人)和L140R。这些突变改变了Lamin A/C中相对保守的残基。L140R突变患者的成纤维细胞中，形态发生变化和层蛋白错位的核比例显著增加。具有LMNA突变的非典型Werner综合征患者的表型比那些因突变WRN而导致的疾病患者更严重。解释我们的发现表明，Werner综合征在分子上是异质性的，这种疾病的一个子集可以被判断为椎板病。
Background Werner's syndrome is a progeroid syndrome caused by mutations at the WRN helicase locus. Some features of this disorder are also present in laminopathies caused by mutant LMNA encoding nuclear lamin A/C. Because of this similarity, we sequenced LMNA in individuals with atypical Werner's syndrome (wild-type WRN).Methods Of 129 index patients referred to our international registry for molecular diagnosis of Werner's syndrome, 26 (20%) had wildtype WRN coding regions and were categorised as having atypical Werner's syndrome on the basis of molecular criteria. We sequenced all exons of LMNA in these individuals. Mutations were confirmed at the mRNA level by RT-PCR sequencing. In one patient in whom an LMNA mutation was detected and fibroblasts were available, we established nuclear morphology and subnuclear localisation.Findings In four (15%) of 26 patients with atypical Werner's syndrome, we noted heterozygosity for novel missense mutations in LMNA, specifically A57P, R133L (in two people), and L140R. The mutations altered relatively conserved residues within lamin A/C. Fibroblasts from the patient with the L140R mutation had a substantially enhanced proportion of nuclei with altered morphology and mislocalised lamins. Individuals with atypical Werner's syndrome with mutations in LMNA had a more severe phenotype than did those with the disorder due to mutant WRN.Interpretation Our findings indicate that Werner's syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.