Transient Infantile Hypertriglyceridemia, Fatty Liver, and Hepatic Fibrosis Caused by Mutated GPD1, Encoding Glycerol-3-Phosphate Dehydrogenase 1
Transient Infantile Hypertriglyceridemia, Fatty Liver, and Hepatic Fibrosis Caused by Mutated GPD1, Encoding Glycerol-3-Phosphate Dehydrogenase 1
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DOI：
10.1016/j.ajhg.2011.11.028
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发表时间：
2012-01-13
影响因子：
9.8
通讯作者：
Shamir, Raanan
中科院分区：
文献类型：
--
作者：
Basel-Vanagaite, Lina;Zevit, Noam;Shamir, Raanan
在不到5%的病例中发现了原发性遗传性高甘油三酯血症的分子基础。单基因血脂异常的研究有可能揭示关键的代谢途径。我们描述了一种迄今未报道的疾病，在10个个体中表现为中度至重度短暂性儿童高甘油三酯血症和脂肪肝，随后是肝纤维化，并鉴定了导致这种情况的突变基因。我们进行了基于SNP阵列的纯合子定位，在染色体12q13.12区域发现了一个大的连续纯合子片段。候选区域包含35个已被列入人类在线孟德尔遗传（Online Mendelian Inheritance in Man， OMIM）的基因和27个其他基因。我们进行了候选基因测序，筛选了临床受影响的个体（患有高甘油三酯血症的儿童和成人）以及GPD1突变的健康队列，GPD1编码甘油-3-磷酸脱氢酶1。突变分析显示一个纯合剪接突变，C .361- 1g >C，导致10个受影响个体的mRNA剪接异常。这种突变预计会导致截断的蛋白质缺乏必要的保守残基，包括负责初始底物识别的功能位点。通过测量过表达正常和突变GPD1 cDNA的HepG2（肝细胞癌）细胞系的细胞内胆固醇和甘油三酯浓度以及甘油三酯分泌来评估突变的功能后果。与野生型GPD1过表达相比，突变型GPD1在HepG2细胞中过表达导致甘油三酯分泌增加（p = 0.01）。这一发现支持了所鉴定突变的致病性。
The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.