Yeung R S, Katsetos C D, Klein-Szanto A
Division of Medical Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Am J Pathol. 1997 Nov;151(5):1477-86.
Tuberous sclerosis (TSC) is an autosomal dominant syndrome that is linked to two genetic loci: TSC1 (9q34) and TSC2 (16p13). Brain manifestations such as cortical tubers and subependymal hamartoma/giant cell astrocytomas are major causes of TSC-related morbidity. In this study, we describe the central nervous system involvement in a unique rodent model of tuberous sclerosis. The Eker rat carries a spontaneous germline mutation of the TSC2 gene and is predisposed to multiple neoplasia. In a series of 45 adult Eker carriers (TSC2 +/-), three types of focal intracranial lesions were found, of which the subependymal and subcortical hamartomas were most prevalent (65%). There exist remarkable phenotypic similarities between the Eker rat and human subependymal lesions. Our study indicates that the predominant cellular phenotype of the subependymal hamartomas is astroglial and suggests that the neuronal contribution within these lesions is, in part, the result of pre-existing myelinated axons. The hamartomas did not show evidence of loss of the wild-type TSC2 allele; it remains to be determined whether TSC2 inactivation is necessary for their pathogenesis. This genetically-defined rodent model may be useful in elucidating the molecular and developmental basis of the subependymal giant cell astrocytoma in humans.
结节性硬化症（TSC）是一种常染色体显性综合征，与两个基因位点相关：TSC1（9q34）和TSC2（16p13）。脑皮质结节和室管膜下错构瘤/巨细胞星形细胞瘤等脑部表现是TSC相关发病的主要原因。在本研究中，我们描述了结节性硬化症一种独特啮齿动物模型中的中枢神经系统受累情况。艾克大鼠携带TSC2基因的自发种系突变，易患多种肿瘤。在45只成年艾克大鼠携带者（TSC2+/-）系列中，发现了三种类型的局灶性颅内病变，其中室管膜下和皮质下错构瘤最为常见（65%）。艾克大鼠与人类室管膜下病变之间存在显著的表型相似性。我们的研究表明，室管膜下错构瘤的主要细胞表型是星形胶质细胞，并提示这些病变中的神经元成分部分是已有髓鞘轴突的结果。错构瘤未显示野生型TSC2等位基因缺失的证据；TSC2失活对其发病机制是否必要仍有待确定。这种基因定义的啮齿动物模型可能有助于阐明人类室管膜下巨细胞星形细胞瘤的分子和发育基础。
