Lessel Davor, Saha Bidisha, Hisama Fuki, Kaymakamzade Bahar, Nurlu Gulay, Gursoy-Özdemir Yasemin, Thiele Holger, Nürnberg Peter, Martin George M, Kubisch Christian, Oshima Junko
Institute of Human Genetics, University of Ulm, Ulm, Germany.
Am J Med Genet A. 2014 Oct;164A(10):2510-3. doi: 10.1002/ajmg.a.36664. Epub 2014 Jul 2.
We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.
我们描述了一名28岁的土耳其男子，其父母为近亲结婚，他表现出衰老的外貌，头发过早变白，皮肤呈硬皮病样，患有痉挛性截瘫且明显残疾。先证者及其父母均为WRN基因突变的杂合子，但这无法解释他的症状。对先证者血液DNA进行外显子组测序显示，SAMHD1基因第5内含子存在纯合的c.626-1G > C突变，该基因编码一种参与调节细胞内脱氧核苷酸三磷酸池的三磷酸水解酶，且在艾卡迪-古铁雷斯综合征中发生突变。RNA研究证实外显子6存在异常剪接，家族研究表明父母双方均为该突变的杂合子。我们得出结论，SAMHD1基因突变——除了在艾卡迪-古铁雷斯综合征中导致早发型脑病——可能还会出现类似于沃纳综合征的适度加速衰老迹象。WRN基因座杂合性在何种程度上可能改变双等位基因SAMHD1突变的效应尚不清楚。可以想象，这两种突变的协同作用可能是导致这种异常表型的原因。
