COL4A1突变会导致神经肌肉疾病，并伴有组织特异性机制异质性。,American Journal of Human Genetics

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COL4A1突变会导致神经肌肉疾病，并伴有组织特异性机制异质性。
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-05-02 , DOI: 10.1016/j.ajhg.2019.03.007
Cassandre Labelle-Dumais ₁ , Vera Schuitema ₁ , Genki Hayashi ₁ , Kendall Hoff ₁ , Wenhui Gong ₂ , Dang Q Dao ₁ , Erik M Ullian ₁ , Peter Oishi ₂ , Marta Margeta ₃ , Douglas B Gould ₄

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IV型胶原蛋白的alpha 1和alpha 2链形成代表基础基底膜成分的异三聚体（[α1（IV）]2α2（IV））。显着的COL4A1和COL4A2突变会导致多系统疾病，其特征是临床异质性和可变表达，并且通常以存在眼，肾和肌肉受累的脑血管疾病为特征。尽管在多达三分之一的具有COL4A1和COL4A2突变的个体以及在COL4A1和COL4A2直系同源基因突变的动物模型中报告了肌肉病理学的事实，但与COL4A1相关的肌病的病理生理机制尚不清楚。通常，突变被认为会削弱[α1（IV）]2α2（IV）的分泌。发病机理是否是由于细胞内滞留，细胞外缺乏，或基膜中突变蛋白的存在，代表了知识上的重要空白和发展针对性干预的主要障碍。我们报告Col4a1突变小鼠发展模拟人类疾病的进行性神经肌肉病理。我们证明了独立的肌肉，神经和血管损伤会导致神经肌病，并且组织之间存在机械异质性。重要的是，我们提供了COL4A1功能子域对组织特异性病理学具有不成比例的意义的证据，并证明了旨在促进[α1（IV）]2α2（IV）分泌的潜在治疗策略可以以依赖突变的方式改善或加剧肌病。。这些数据对于基于基因型的临床结果预测具有重要的翻译意义，基于机制的干预措施的开发，以及用于临床试验的基因分层。总体而言，我们的数据强调了[α1（IV）]2α2（IV）网络作为多功能信号平台的重要性，并表明等位基因和组织特异性机制异质性有助于COL4A1和COL4A2突变的可变表达。

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COL4A1 Mutations Cause Neuromuscular Disease with Tissue-Specific Mechanistic Heterogeneity.

Collagen type IV alpha 1 and alpha 2 chains form heterotrimers ([α1(IV)]2α2(IV)) that represent a fundamental basement membrane constituent. Dominant COL4A1 and COL4A2 mutations cause a multisystem disorder that is marked by clinical heterogeneity and variable expressivity and that is generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular involvement. Despite the fact that muscle pathology is reported in up to one-third of individuals with COL4A1 and COL4A2 mutations and in animal models with mutations in COL4A1 and COL4A2 orthologs, the pathophysiological mechanisms underlying COL4A1-related myopathy are unknown. In general, mutations are thought to impair [α1(IV)]2α2(IV) secretion. Whether pathogenesis results from intracellular retention, extracellular deficiency, or the presence of mutant proteins in basement membranes represents an important gap in knowledge and a major obstacle for developing targeted interventions. We report that Col4a1 mutant mice develop progressive neuromuscular pathology that models human disease. We demonstrate that independent muscular, neural, and vascular insults contribute to neuromyopathy and that there is mechanistic heterogeneity among tissues. Importantly, we provide evidence of a COL4A1 functional subdomain with disproportionate significance for tissue-specific pathology and demonstrate that a potential therapeutic strategy aimed at promoting [α1(IV)]2α2(IV) secretion can ameliorate or exacerbate myopathy in a mutation-dependent manner. These data have important translational implications for prediction of clinical outcomes based on genotype, development of mechanism-based interventions, and genetic stratification for clinical trials. Collectively, our data underscore the importance of the [α1(IV)]2α2(IV) network as a multifunctional signaling platform and show that allelic and tissue-specific mechanistic heterogeneities contribute to the variable expressivity of COL4A1 and COL4A2 mutations.

更新日期：2019-05-16

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