CARS2 中的纯合剪接位点突变与进行性肌阵挛性癫痫有关。
A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.
机构信息
From the Department of Epileptology and Life & Brain Center (K.H., G.Z., S.M.-H., C.E.E., W.S.K.), University of Bonn; Department of Neuropediatrics and Muscle Disorders (J.K., R.K.), University of Freiburg; Cologne Center for Genomics (A.-K.R., H.T., P.N., T.S.), Center for Molecular Medicine Cologne (P.N.), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (P.N.), University of Cologne, Germany; Genetic Department (O.O.), Institute of Experimental Medicine (DETAE), Istanbul University, Turkey; Department of Neurology and Epileptology (Y.W., F.B., H.L.), Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
出版信息
Neurology. 2014 Dec 2;83(23):2183-7. doi: 10.1212/WNL.0000000000001055. Epub 2014 Oct 31.
OBJECTIVE
We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline.
METHODS
After excluding the presence of pathogenic mitochondrial DNA mutations, whole-exome sequencing of blood DNA from the index patient was performed. Detected homozygous mutations and their cosegregation were confirmed by Sanger sequencing. CARS2 (cysteinyl-tRNA synthetase 2, mitochondrial) messenger RNA analysis was performed by reverse transcription PCR and sequencing.
RESULTS
We identified a homozygous c.655G>A mutation in the CARS2 gene cosegregating in the family. The mutation is localized at the last nucleotide of exon 6 and thus is predicted to cause aberrant splicing. Analysis of the CARS2 messenger RNA showed that the presence of the mutation resulted in removal of exon 6. This leads to an in-frame deletion of 28 amino acids in a conserved sequence motif of the protein involved in stabilization of the acceptor end hairpin of tRNA(Cys).
CONCLUSION
CARS2 is a novel disease gene associated with a severe progressive myoclonic epilepsy most resembling MERRF syndrome.
目的
我们报道了一个有 2 名受影响个体的近亲家族，其临床症状与 MERRF（肌阵挛性癫痫伴破碎红纤维）综合征非常相似，包括严重的肌阵挛性癫痫、进行性痉挛性四肢瘫痪、进行性视力和听力损害以及进行性认知能力下降。
方法
在排除致病性线粒体 DNA 突变存在后，对先证者的血液 DNA 进行全外显子组测序。通过 Sanger 测序证实检测到的纯合突变及其共分离。通过反转录 PCR 和测序进行 CARS2（半胱氨酰-tRNA 合成酶 2，线粒体）信使 RNA 分析。
结果
我们在该家族中发现了 CARS2 基因的纯合 c.655G>A 突变，该突变定位于外显子 6 的最后一个核苷酸，因此预计会导致异常剪接。CARS2 信使 RNA 的分析表明，该突变的存在导致外显子 6 的缺失。这导致了蛋白中与稳定 tRNA(Cys)受体末端发夹相关的保守序列基序的 28 个氨基酸的框内缺失。
结论
CARS2 是一种与最类似于 MERRF 综合征的严重进行性肌阵挛性癫痫相关的新型疾病基因。
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