A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.
A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome.
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DOI：
10.1136/jmedgenet-2016-104295
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发表时间：
2017-03
影响因子：
4
通讯作者：
Gordon LB
中科院分区：
文献类型：
--
作者：
Bar DZ;Arlt MF;Brazier JF;Norris WE;Campbell SE;Chines P;Larrieu D;Jackson SP;Collins FS;Glover TW;Gordon LB
Hutchinson-Gilford早衰症(HGPS)是一种致命的散发性常染色体显性早衰病，由单碱基突变引起，该突变优化了LMNA基因第11外显子内的一个隐蔽剪接点。由此产生的致病蛋白孕激素起着显性负性作用。疾病的严重程度部分取决于孕激素水平。我们报告了一种新的形式的体细胞嵌合体，其中一个孩子拥有两个细胞群体，具有相同核苷酸的不同HGPS致病突变-一个产生严重的HGPS，一个产生轻度的HGPS。先证者具有中间表型。这种嵌合体最初是在桑格测序显示血液DNA中存在C.1968+2T>；A突变，以及培养的成纤维细胞DNA中存在c.1968+2T>；C突变时发现的。对先证者血液进行DNA深度测序，发现4.7%C.1968+2T>；C突变，41.3%c.1968+2T>；A突变。我们假设胚系突变是C.1968+2T>；A，但在早期发育过程中发生了一次挽救事件，其中1968+2处的体细胞突变从A到C提供了选择优势。这种类型的嵌合体是由同一核苷酸中第二个但较温和的致病突变导致的部分表型救援事件，以前没有任何疾病的特征。
Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels. We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide—one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation. We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease.