Novel compound heterozygous SUCLG1 variants may contribute to mitochondria DNA depletion syndrome-9.
Novel compound heterozygous SUCLG1 variants may contribute to mitochondria DNA depletion syndrome-9.
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DOI：
10.1002/mgg3.2010
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发表时间：
2022-09
影响因子：
2
通讯作者：
中科院分区：
文献类型：
--
作者：
琥珀酸-辅酶a连接酶/合成酶（SCS）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。SUCLG1是编码SCS酶α亚基的核基因，在维持mtDNA的完整性和稳定性中起关键作用，其变异与线粒体DNA耗竭综合征9 （MTDPS9）有关。在这项研究中，我们报道了一名来自中国的具有MTDPS9临床特征的婴儿。采用全外显子组测序（WES）确定遗传原因。采用生物信息学分析和mtDNA水平检测评估致病性。先证者表现为低张力、乳酸性酸中毒、轻度甲基丙二酸尿、听力损失和精神运动迟缓。WES在第6外显子C . 601a >G （p.R201G）和第8外显子C . 871g >C （p.A291P）中发现了新的复合杂合SUCLG1变异。计算分析预测，这些错义变异可能会改变SUCLG1的结构稳定性和线粒体易位。与对照组相比，qRT‐PCR显示先证者mtDNA含量减少68%。SUCLG1中新的复合杂合变异体C . 601a >G （p.R201G）和C . 871g >C （p.A291P）可能导致该家族的MTDPS9。本研究结果对SCS缺乏性疾病的分子诊断、遗传咨询和临床管理具有一定的指导意义。SUCLG1中新的复合杂合变异体C . 601a >G （p.R201G）和C . 871g >C （p.A291P）可能是线粒体DNA耗损综合征的原因9。本研究结果可为SCS缺乏症的分子诊断、遗传咨询和临床治疗提供参考。
Succinate‐CoA ligase/synthetase (SCS) deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Variants in SUCLG1, the nuclear gene encoding the alpha subunit of the SCS enzyme playing a pivotal role in maintaining mtDNA integrity and stability, are associated with mitochondrial DNA depletion syndrome 9 (MTDPS9). In this study, we reported an infant with clinical features of MTDPS9 from China. Whole exome sequencing (WES) was used to identify the genetic cause. Bioinformatic analysis and mtDNA level detection were performed to assess pathogenicity. The proband manifested with hypotonia, lactic acidosis, mild methylmalonic aciduria, hearing loss and psychomotor retardation. WES identified new compound heterozygous SUCLG1 variants of c.601A>G (p.R201G) in exon 6 and c.871G>C (p.A291P) in exon 8. Computational analysis predicted that these missense variants might alter structure stability and mitochondrial translocation of SUCLG1. qRT‐PCR showed 68% depletion of mtDNA content in proband as compared to controls. Novel compound heterozygous variants c.601A>G (p.R201G) and c.871G>C (p.A291P) in SUCLG1 may cause MTDPS9 in this family. Our finding should be helpful for molecular diagnosis, genetic counseling and clinical management of SCS deficiency disorders. Novel compound heterozygous variants c.601A>G ( p.R201G) and c.871G>C (p.A291P) in SUCLG1 may be responsible for mitochondrial DNA depletion syndrome 9. Our finding should be helpful for molecular diagnosis, genetic counseling and clinical management of SCS deficiency disorder.
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