Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
Ariagene Medical Genetics Laboratory, Qom, Iran.
Mol Genet Genomic Med. 2020 Nov;8(11):e1507. doi: 10.1002/mgg3.1507. Epub 2020 Sep 23.
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 gene (HMGCS2) encodes a mitochondrial enzyme catalyzing the first reaction of ketogenesis metabolic pathway which provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are responsible for HMG-CoA synthase deficiency (HMGCSD). The aim of present study was to investigate the association of mutation in the HMGCS2 gene with HMGCSD in a patient with atypical symptoms.
The clinical and genetic features of an 8-months-old girl with HMGCSD were evaluated. Molecular genetic testing was conducted using whole-exome sequencing (WES) in order to identify potential disease-causing mutation. The WES finding was confirmed by the polymerase chain reaction (PCR) amplification of the target sequence carried out for the patient and her parents. The PCR products were subjected to direct sequencing using forward and reverse specific primers corresponding to the HMGCS2 gene.
A novel homozygous missense mutation (c.266G>A p.Gly89Asp) was detected in the HMGCS2 gene. Sanger sequencing along with co-segregation analysis of all family members confirmed this novel pathogenic germline mutation. The mutant gene was found to be pathogenic by bioinformatics analysis.
To our best knowledge, this is the first report of HMGCSD in Iran which would expand our knowledge about the mutational spectrum of the HMGCS2 gene and the phenotype variations of the disease.
3-羟-3-甲基戊二酰辅酶 A（HMG-CoA）合酶 2 基因（HMGCS2）编码一种线粒体酶，催化酮体生成代谢途径的第一步反应，在碳水化合物缺乏时（如禁食）为各种器官提供脂源性能量。该基因的突变导致 HMG-CoA 合酶缺乏症（HMGCSD）。本研究旨在探讨 HMGCS2 基因突变与具有非典型症状患者的 HMGCSD 之间的关系。
评估了一名 8 个月大的 HMGCSD 患儿的临床和遗传特征。采用全外显子组测序（WES）进行分子遗传学检测，以确定潜在的致病突变。WES 发现通过针对患者及其父母的目标序列进行聚合酶链反应（PCR）扩增得到确认。使用与 HMGCS2 基因相对应的正向和反向特异性引物对 PCR 产物进行直接测序。
在 HMGCS2 基因中检测到一种新的纯合错义突变（c.266G>A p.Gly89Asp）。对所有家庭成员进行 Sanger 测序和共分离分析证实了这种新的致病性种系突变。通过生物信息学分析发现突变基因具有致病性。
据我们所知，这是伊朗首例 HMGCSD 的报道，这将扩展我们对 HMGCS2 基因突变谱和疾病表型变异的认识。
