Departments of Biochemistry and Medicine, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Clin Genet. 2019 Feb;95(2):199-209. doi: 10.1111/cge.13455. Epub 2018 Oct 23.
The nuclear lamins are important members of the intermediate filament (IF) family of proteins, involved in structural support and regulation of the nuclear lamina. Different mutations in various members of these type V IF proteins produce a staggering range of human disease phenotypes, which collectively have been termed "laminopathies." Compelling examples are the wide range of inherited disorders that result from rare variants in LMNA encoding lamin A/C. These laminopathies include skeletal and cardiac muscle disorders, neuropathies, multisystem progeroid disorders, and lipodystrophies, of which the latter are associated with several metabolic complications. Functions of lamin A/C that have been shown to be compromised by distinct mutations in LMNA include loss of nuclear structural integrity, altered interaction with transcription factors, and changes to post-translational processing of pre-lamins. Recently, evidence has emerged that certain LMNA mutations, such as those causing partial lipodystrophy, alter the interaction between chromatin and lamin A, in turn affecting the spatial orientation and distribution of chromatin within the nucleus. Because chromatin organization is exquisitely tied to global patterns of gene expression, the findings suggest a novel mechanism to explain the tissue-specific impact of a subset of laminopathy-associated LMNA mutations.
核纤层蛋白是中间丝（IF）蛋白家族的重要成员，参与核纤层的结构支撑和调节。这些 V 型 IF 蛋白的不同成员中的不同突变产生了惊人范围的人类疾病表型，这些表型统称为“核纤层病”。引人注目的例子是，由于编码核纤层蛋白 A/C 的 LMNA 中的罕见变异导致的广泛遗传性疾病。这些核纤层病包括骨骼肌和心肌疾病、神经病、多系统进行性骨化障碍和脂肪营养不良，其中后者与多种代谢并发症有关。已显示由 LMNA 中的不同突变引起的核纤层蛋白 A/C 的功能受损包括核结构完整性丧失、与转录因子的相互作用改变以及核纤层前体的翻译后加工改变。最近，有证据表明，某些 LMNA 突变，如导致部分脂肪营养不良的突变，改变了染色质与核纤层 A 之间的相互作用，进而影响了染色质在核内的空间定向和分布。由于染色质组织与基因表达的全局模式紧密相关，这些发现提出了一种新的机制来解释一组与核纤层病相关的 LMNA 突变的组织特异性影响。
