新型复合杂合 SUCLG1 变异可能导致线粒体 DNA 耗竭综合征 9 型。
Novel compound heterozygous SUCLG1 variants may contribute to mitochondria DNA depletion syndrome-9.
机构信息
Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
出版信息
Mol Genet Genomic Med. 2022 Sep;10(9):e2010. doi: 10.1002/mgg3.2010. Epub 2022 Jun 28.
BACKGROUND
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).
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
琥珀酰辅酶 A 连接酶/合成酶（SCS）缺乏症是导致脑肌病伴线粒体 DNA 耗竭和轻度甲基丙二酸血症的原因。SUCLG1 核基因突变，该基因编码 SCS 酶的α亚基，在维持线粒体 DNA 完整性和稳定性方面发挥关键作用，与线粒体 DNA 耗竭综合征 9 型（MTDPS9）相关。
方法
本研究报道了一例来自中国的 MTDPS9 患儿。采用外显子组测序（WES）鉴定致病基因。通过生物信息学分析和 mtDNA 水平检测评估致病性。
结果
先证者表现为肌张力低下、乳酸酸中毒、轻度甲基丙二酸尿症、听力损失和精神运动发育迟缓。WES 发现 SUCLG1 外显子 6 中的 c.601A>G（p.R201G）和外显子 8 中的 c.871G>C（p.A291P）复合杂合变异。计算分析预测这些错义变异可能改变 SUCLG1 的结构稳定性和线粒体易位。qRT-PCR 显示与对照组相比，先证者 mtDNA 含量减少了 68%。
结论
SUCLG1 中的新型复合杂合变异 c.601A>G（p.R201G）和 c.871G>C（p.A291P）可能导致该家系的 MTDPS9。我们的发现有助于 SCS 缺乏症的分子诊断、遗传咨询和临床管理。
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