Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina‐associated proteins predispose to NAFLD and used a candidate gene‐sequencing approach to test for variants in 10 nuclear lamina‐related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina‐related genes (ZMPSTE24, TMPO, SREBF1, SREBF2). The majority of NAFLD patients (>90%) had at least one variant compared to <40% of controls (P < 0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P < 0.0001). Presence of a lamina variant segregated with NAFLD independently of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina‐associated polypeptide‐2 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin–LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin‐binding protein p62/SQSTM1. Conclusion: Several variants in nuclear lamina‐related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (Hepatology 2018;67:1710‐1725).

中文翻译：

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患有非酒精性脂肪肝的双胞胎和兄弟姐妹的核层遗传变异，包括截短的 LAP2

非酒精性脂肪性肝病 (NAFLD) 正在成为许多国家的主要慢性肝病。其发病机制是多因素的，但双胞胎和家族研究表明具有显着的遗传性，目前已知的遗传易感性位点无法完全解释这一点。值得注意的是，编码核纤层蛋白（包括核纤层蛋白）的基因突变会导致脂肪代谢障碍综合征，包括 NAFLD。我们假设核层相关蛋白的变异易患 NAFLD，并使用候选基因测序方法测试 37 对双胞胎和兄弟姐妹的队列中 10 个核层相关基因的变异：21 个人有 NAFLD，53 个人没有 NAFLD。在四个叶片相关基因（ZMPSTE24、TMPO、SREBF1、SREBF2）中鉴定出十二个杂合序列变体。大多数 NAFLD 患者 (> 90%) 至少有一种变异，而对照组的 <40% (P < 0.0001)。当仅考虑保守残基的插入/缺失和变化时，组之间的差异同样显着（>80% 对 <25%；P < 0.0001）。存在独立于 PNPLA3 I148M 多态性与 NAFLD 分离的层变体。在 TMPO 中发现了几种变体，其编码与肝病无关的层板相关多肽-2（LAP2）。其中之一，产生截短的 LAP2 的移码插入，废除了 lamin-LAP2 结合，导致 LAP2 错误定位，改变内源性 lamin 分布，在转染细胞中油酸处理后脂滴积累增加，并导致细胞质与泛素结合蛋白的结合p62/SQSTM1。结论：在一组患有 NAFLD 的双胞胎和兄弟姐妹中发现了核纤层相关基因的几种变异；一种这样的变异导致 LAP2 蛋白截短和细胞培养中的显着表型，代表了 TMPO/LAP2 变异与 NAFLD 的关联，并强调了核层在 NAFLD 中的潜在重要性。（肝病学 2018 年；67：1710-1725）。