The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein
The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein
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DOI：
10.1136/jmg.2009.073445
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发表时间：
2010-10-01
影响因子：
4
通讯作者：
Paquis-Flucklinger, V.
中科院分区：
文献类型：
--
作者：
Rouzier, C.;Le Guedard-Mereuze, S.;Paquis-Flucklinger, V.
背景琥珀酸-辅酶a连接酶缺乏是导致线粒体DNA缺失和轻度甲基丙二酸尿的脑肌病的原因。编码琥珀酸辅酶a连接酶β亚基的基因sucl2突变，迄今为止已在17例患者中报道。编码酶α亚基的SUCLG1突变仅在两个家系中被描述。方法和发现在本研究中，报告了两例不相关的患者携带三种新的SUCLG1致病突变。第一个病人出生时患有严重的疾病。他是复合杂合的错义突变（p.p pro170arg）和C .97+3G>C突变，导致外显子1在一个小基因表达系统中完全跳过。western blot分析证实了SUCLG1的参与，结果显示成纤维细胞中缺乏SUCLG1蛋白。第二例患者的表型较轻，与SUCIA2突变患者相似，并且在12岁时仍然存活。Western blot分析显示，患者成纤维细胞中有残留的SUCLG1蛋白。我们的研究结果表明，导致SUCLG1蛋白完全缺失的SUCLG1突变是导致具有产前表现的非常严重的疾病的原因，而在SUCLG1蛋白残留的患者中发现了sucl2样表型。此外，western blot分析显示，在SUCLG1蛋白缺失的情况下，成纤维细胞中未发现sucl2蛋白。这一结果与sucl2在其异源二聚体伴侣SUCLG1缺失时的降解一致。
Background Succinate-CoA ligase deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Mutations in SUCLA2, the gene encoding a beta subunit of succinate-CoA ligase, have been reported in 17 patients until now. Mutations in SUCLG1, encoding the alpha subunit of the enzyme, have been described in two pedigrees only.Methods and findings In this study, two unrelated patients harbouring three novel pathogenic mutations in SUCLG1 were reported. The first patient had a severe disease at birth. He was compound heterozygous for a missense mutation (p.Pro170Arg) and a c.97+3G>C mutation, which leads to the complete skipping of exon 1 in a minigene expression system. The involvement of SUCLG1 was confirmed by western blot analysis, which showed absence of SUCLG1 protein in fibroblasts. The second patient has a milder phenotype, similar to that of patients with SUCIA2 mutations, and is still alive at 12 years of age. Western blot analysis showed some residual SUCLG1 protein in patient's fibroblasts.Conclusions Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLG1 protein. Furthermore, it is shown that in the absence of SUCLG1 protein, no SUCLA2 protein is found in fibroblasts by western blot analysis. This result is consistent with a degradation of SUCLA2 when its heterodimer partner, SUCLG1, is absent.