Dharmaraj Tejas, Guan Youchen, Liu Julie, Badens Catherine, Gaborit Benedicte, Wilson Katherine L
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
INSERM, MMG, Aix Marseille Université, Marseille, France.
Front Cell Dev Biol. 2019 Apr 5;7:48. doi: 10.3389/fcell.2019.00048. eCollection 2019.
Emerin () and barrier to autointegration factor 1 () each bind A-type lamins () as fundamental components of nuclear lamina structure. Mutations in , and are genetically linked to many tissue-specific disorders including Emery-Dreifuss muscular dystrophy and cardiomyopathy (, ), lipodystrophy, insulin resistance and type 2 diabetes () and progeria (, ). To explore human genetic variation in these genes, we analyzed and alleles in the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals. We identified 13 rare heterozygous BANF1 missense variants (p.T2S, p.H7Y, p.D9N, p.S22R, p.G25E, p.D55N, p.D57Y, p.L63P, p.N70T, p.K72R, p.R75W, p.R75Q, p.G79R), and one homozygous variant (p.D9H). Several variants are known (p.G25E) or predicted (e.g., p.D9H, p.D9N, p.L63P) to perturb BANF1 and warrant further study. Analysis of revealed two previously identified variants associated with adult-onset cardiomyopathy (p.K37del, p.E35K) and one deemed 'benign' in an Emery-Dreifuss patient (p.D149H). Interestingly p.D149H was the most frequent emerin variant in ExAC, identified in 58 individuals (overall allele frequency 0.06645%), of whom 55 were East Asian (allele frequency 0.8297%). Furthermore, p.D149H associated with four 'healthy' traits: reduced triglycerides (-0.336; = 0.0368), reduced waist circumference (-0.321; = 0.0486), reduced cholesterol (0.572; = 0.000346) and reduced LDL cholesterol (-0.599; = 0.000272). These traits are distinct from -associated metabolic disorders and provide the first insight that emerin influences metabolism. We also identified one novel in-frame deletion (p.F39del) and 62 novel emerin missense variants, many of which were relatively frequent and potentially disruptive including p.N91S and p.S143F (∼0.041% and ∼0.034% of non-Finnish Europeans, respectively), p.G156S (∼0.39% of Africans), p.R204G (∼0.18% of Latinx), p.R207P (∼0.08% of South Asians) and p.R221L (∼0.15% of Latinx). Many novel BANF1 variants are predicted to disrupt dimerization or binding to DNA, histones, emerin or A-type lamins. Many novel emerin variants are predicted to disrupt emerin filament dynamics or binding to BANF1, HDAC3, A-type lamins or other partners. These new human variants provide a foundational resource for future studies to test the molecular mechanisms of BANF1 and emerin function, and to understand the link between emerin variant p.D149H and a 'healthy' lipid profile.
Emerin（）和自身整合因子1（）作为核纤层结构的基本组成部分，均与A型核纤层蛋白（）结合。、和的突变在遗传上与许多组织特异性疾病相关，包括埃默里 - 德赖富斯肌营养不良症和心肌病（，）、脂肪营养不良、胰岛素抵抗和2型糖尿病（）以及早衰症（，）。为了探究这些基因中的人类遗传变异，我们分析了外显子聚合联盟（ExAC）队列中60706名无关个体的和等位基因。我们鉴定出13个罕见的杂合BANF1错义变体（p.T2S、p.H7Y、p.D9N、p.S22R、p.G25E、p.D55N、p.D57Y、p.L63P、p.N70T、p.K72R、p.R75W、p.R75Q、p.G79R）以及一个纯合变体（p.D9H）。已知一些变体（p.G25E）或预测（例如p.D9H、p.D9N、p.L63P）会干扰BANF1，值得进一步研究。对的分析揭示了两个先前鉴定出的与成人发病型心肌病相关的变体（p.K37del、p.E35K）以及一个在埃默里 - 德赖富斯患者中被认为是“良性”的变体（p.D149H）。有趣的是，p.D149H是ExAC中最常见的emerin变体，在58名个体中被鉴定出（总体等位基因频率为0.06645%），其中55名是东亚人（等位基因频率为0.8297%）。此外，p.D149H与四个“健康”特征相关：甘油三酯降低（-0.33；=0.0368）、腰围减小（-0.321；=0.0486）、胆固醇降低（-0.572；=0.000346）和低密度脂蛋白胆固醇降低（-0.599；=0.000272）。这些特征与相关的代谢紊乱不同，首次表明emerin会影响新陈代谢。我们还鉴定出一个新的框内缺失（p.F39del）和62个新的emerin错义变体，其中许多相对常见且可能具有破坏性，包括p.N91S和p.S143F（分别约占非芬兰欧洲人的0.041%和约0.034%）、p.G156S（约占非洲人的0.39%）、p.R204G（约占拉丁裔的0.18%）、p.R207P（约占南亚人的0.08%）和p.R221L（约占拉丁裔的0.15%）。许多新的BANF1变体预计会破坏二聚化或与DNA、组蛋白、emerin或A型核纤层蛋白的结合。许多新的emerin变体预计会破坏emerin丝的动态变化或与BANF1、HDAC3、A型核纤层蛋白或其他伙伴的结合。这些新的人类变体为未来研究测试BANF1和emerin功能的分子机制以及理解emerin变体p.D149H与“健康”脂质谱之间的联系提供了基础资源。
