Identification and functional characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease
Identification and functional characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease
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遗传性非酒精性脂肪肝的罕见 MTTP 变异的鉴定和功能特征
DOI：
10.1101/2021.07.22.21260356
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Grove J
中科院分区：
文献类型：
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作者：
Grove J
背景和目的非酒精性脂肪性肝病(NAFLD)是一种复杂的特征，其全球患病率估计为25%。我们的目的是在没有肥胖和2型糖尿病等常见危险因素的情况下，确定一个进行性NAFLD家系导致肝硬化、失代偿和发展为肝细胞癌的潜在的遗传变异。方法通过外显子序列测定和基因组比较来确定可能的原因变异。我们广泛地描述了家族成员的临床表型和餐后代谢反应，并与健康的非携带者和野生型NAFLD患者进行了比较。变异体表达的肝细胞样细胞(HLCs)来源于人类诱导的多能干细胞，来源于纯合子供体皮肤成纤维细胞。结果我们在MTTP中发现了一个罕见的原因变异，编码微粒体甘油三酯转移蛋白(MTP)的C.1691T>；C p.I564T(Rs745447480)与进行性非酒精性脂肪性肝病相关，与代谢综合征无关。虽然MTTP的其他已描述的突变导致非脂蛋白血症，但无论是纯合子还是杂合子都没有表现出这种严重疾病的特征表现。与野生型细胞相比，纯合子供者来源的HLCs具有较低的脂蛋白ApoB分泌。结论我们发现并鉴定了MTTP的一种罕见的原因变异和MTTP的纯合性。I564T与进展性NAFLD相关，无其他表现为非脂蛋白血症。
Background and AimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like-cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays.ResultsWe identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species.ConclusionWe have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.