Gutmann D H, Hirbe A C, Haipek C A
Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Hum Mol Genet. 2001 Jul 1;10(14):1519-29. doi: 10.1093/hmg/10.14.1519.
Neurofibromatosis 2 (NF2) is a tumor predisposition syndrome in which affected individuals develop nervous system tumors at an increased frequency. The most common tumor in individuals with NF2 is the schwannoma, which is composed of neoplastic Schwann cells lacking NF2 gene expression. Moreover, inactivation of the NF2 gene is observed in nearly all sporadic schwannomas, suggesting that the NF2 gene is a critical growth regulator for Schwann cells. In an effort to gain insights into the function of the NF2 gene product, merlin or schwannomin, we performed a detailed functional analysis of eight naturally occurring non-conservative missense mutations in the NF2 gene. Using a regulatable expression system in rat schwannoma cells, we analyzed proliferation, actin cytoskeleton-mediated events and merlin folding. In this report, we demonstrate that mutations clustered in the predicted alpha-helical region did not impair the function of merlin whereas those in either the N- or C-terminus of the protein rendered merlin inactive as a negative growth regulator. These results suggest that the key functional domains of merlin lie within the highly conserved FERM domain and the unique C-terminus of the protein.
神经纤维瘤病2型（NF2）是一种肿瘤易感综合征，患病个体发生神经系统肿瘤的频率增加。NF2患者中最常见的肿瘤是神经鞘瘤，它由缺乏NF2基因表达的肿瘤性施万细胞组成。此外，在几乎所有散发性神经鞘瘤中都观察到NF2基因失活，这表明NF2基因是施万细胞的关键生长调节因子。为了深入了解NF2基因产物默林（merlin）或施万神经瘤蛋白（schwannomin）的功能，我们对NF2基因中的八个自然发生的非保守错义突变进行了详细的功能分析。利用大鼠神经鞘瘤细胞中的可调节表达系统，我们分析了增殖、肌动蛋白细胞骨架介导的事件以及默林的折叠情况。在本报告中，我们证明聚集在预测的α螺旋区域的突变不会损害默林的功能，而那些位于该蛋白N端或C端的突变会使默林作为负生长调节因子失去活性。这些结果表明，默林的关键功能域位于该蛋白高度保守的FERM结构域和独特的C端内。
