Department of Cell and Developmental Biology, Biocenter, University of Würzburg; Würzburg, Germany.
Nucleus. 2012 Sep-Oct;3(5):463-74. doi: 10.4161/nucl.21676. Epub 2012 Aug 16.
During recent years a number of severe clinical syndromes, collectively termed laminopathies, turned out to be caused by various, distinct mutations in the human LMNA gene. Arising from this, remarkable progress has been made to unravel the molecular pathophysiology underlying these disorders. A great benefit in this context was the generation of an A-type lamin deficient mouse line (Lmna (-/-) ) by Sullivan and others, ( 1) which has become one of the most frequently used models in the field and provided profound insights to many different aspects of A-type lamin function. Here, we report the unexpected finding that these mice express a truncated Lmna gene product on both transcriptional and protein level. Combining different approaches including mass spectrometry, we precisely define this product as a C-terminally truncated lamin A mutant that lacks domains important for protein interactions and post-translational processing. Based on our findings we discuss implications for the interpretation of previous studies using Lmna (-/-) mice and the concept of human laminopathies.
近年来，一些严重的临床综合征，统称为层粘连蛋白病，被证明是由人类 LMNA 基因的各种不同的、明显的突变引起的。由此，在分子病理生理学方面取得了显著的进展。在这方面，一个很大的好处是沙利文等人（1）产生了一种 A 型层粘连蛋白缺陷的小鼠系（Lmna（-/-）），这已经成为该领域最常用的模型之一，并为 A 型层粘连蛋白功能的许多不同方面提供了深刻的见解。在这里，我们报告了一个意想不到的发现，即这些小鼠在转录和蛋白质水平上都表达一种截断的 Lmna 基因产物。通过结合包括质谱在内的不同方法，我们精确地将该产物定义为一种 C 端截断的核纤层蛋白 A 突变体，它缺乏对蛋白质相互作用和翻译后加工很重要的结构域。基于我们的发现，我们讨论了对使用 Lmna（-/-）小鼠的先前研究的解释以及人类层粘连蛋白病概念的影响。
