Chen Lishan, Lee Lin, Kudlow Brian A, Dos Santos Heloisa G, Sletvold Olav, Shafeghati Yousef, Botha Eleanor G, Garg Abhimanyu, Hanson Nancy B, Martin George M, Mian I Saira, Kennedy Brian K, Oshima Junko
Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
Lancet. 2003 Aug 9;362(9382):440-5. doi: 10.1016/S0140-6736(03)14069-X.
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).
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.
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.
Our findings indicate that Werner's syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.
沃纳综合征是一种由WRN解旋酶基因座突变引起的早老症样综合征。这种疾病的一些特征也存在于由编码核纤层蛋白A/C的突变型LMNA引起的核纤层蛋白病中。由于这种相似性，我们对非典型沃纳综合征（野生型WRN）患者的LMNA进行了测序。
在转诊至我们国际登记处进行沃纳综合征分子诊断的129例索引患者中，26例（20%）的WRN编码区为野生型，根据分子标准被归类为患有非典型沃纳综合征。我们对这些个体的LMNA所有外显子进行了测序。通过逆转录聚合酶链反应测序在mRNA水平确认突变。在一名检测到LMNA突变且有可用成纤维细胞的患者中，我们确定了核形态和核内亚定位。
在26例非典型沃纳综合征患者中的4例（15%）中，我们发现LMNA存在新的错义突变杂合性，具体为A57P、R133L（两人）和L140R。这些突变改变了核纤层蛋白A/C内相对保守的残基。携带L140R突变的患者的成纤维细胞中，形态改变和核纤层蛋白定位错误的细胞核比例显著增加。LMNA突变的非典型沃纳综合征患者的表型比由突变型WRN引起的疾病患者更严重。
我们的研究结果表明，沃纳综合征在分子水平上具有异质性，该疾病的一个亚组可被判定为核纤层蛋白病。
