Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome
Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome
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DOI：
10.1038/nature01629
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发表时间：
2003-05-15
期刊：
影响因子：
64.8
通讯作者：
Collins, FS
中科院分区：
文献类型：
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作者：
Eriksson, M;Brown, WT;Collins, FS
Hutchinson-Gilford早衰综合征（HGPS）是一种罕见的遗传性疾病，其特征令人想起明显的过早衰老（1，2）。在这里，我们提出了核纤层蛋白A（LMNA）突变作为这种疾病的原因的证据。HGPS基因最初定位于染色体1 q，通过观察两例1 q的单亲同二体性（从一个父母遗传该材料的两个拷贝）和一例6兆碱基的父亲间质缺失。LMNA的测序位于该区间，并且先前与其他几种遗传性疾病有关（3，4），显示20例HGPS经典病例中有18例在外显子11内具有相同的从头（即，新出现的而非遗传的）单碱基取代，G608 G（GGC > GGT）。另一例在同一密码子内发现了不同的取代。这两种突变都导致外显子11内隐蔽剪接位点的激活，导致产生缺失羧基末端附近50个氨基酸的蛋白质产物。HGPS成纤维细胞与针对核纤层蛋白A的抗体的免疫荧光显示，许多细胞显示出可见的核膜异常。这种疾病的分子基础的发现可能会揭示人类衰老的普遍现象。
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing(1,2). Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q - the inheritance of both copies of this material from one parent - and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders(3,4), revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo ( that is, newly arisen and not inherited) single-base substitution, G608G( GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.