Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1
Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1
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DOI：
10.1086/519562
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发表时间：
2007-08-01
影响因子：
9.8
通讯作者：
Messiaen, Ludwine
中科院分区：
文献类型：
--
作者：
Maertens, Ophelia;De Schepper, Sofie;Messiaen, Ludwine
事实证明，阐明 I 型神经纤维瘤病 (NFI) 相关症状发生的生物学框架非常困难。复杂的因素包括 NFI 基因的大小、多个 NFI 假基因的存在、细胞类型之间复杂的相互作用以及体内所有细胞的 NFI 单倍体不足状态。在这里，我们调查了三名具有不同 NFI 相关临床表现的患者（仅神经纤维瘤、仅色素变化以及两种症状的关联）。对每位患者的各种组织和细胞类型进行了全面的定量检测，能够检测低百分比的 NFI 突变。该方法证实了神经纤维瘤雪旺细胞中双等位基因 NF1 失活，并首次证明了 NF1 相关咖啡斑疹黑素细胞中双等位基因 NF1 失活。有趣的是，这两种疾病特征甚至在以 NF1 野生型细胞为主的背景下也会出现。总之，这些数据提供了分子证据，表明（1）患者的独特临床表现是由于 NF1 突变的嵌合性所致；（2）嵌合表型反映了胚胎时间，因此反映了参与体细胞 W I 突变的神经嵴衍生细胞类型。对受影响细胞类型的研究为了解特定 NF1 相关疾病特征背后的发育概念提供了重要见解，并为改善嵌合型 NFI 个体的诊断和遗传咨询开辟了途径。
Elucidation of the biological framework underlying the development of neurofibromatosis type I (NFI)-related symptoms has proved to be difficult. Complicating factors include the large size of the NFI gene, the presence of several NFI pseudogenes, the complex interactions between cell types, and the NFI-haploinsufficient state of all cells in the body. Here, we investigate three patients with distinct NFI-associated clinical manifestations (neurofibromas only, pigmentary changes only, and association of both symptoms). For each patient, various tissues and cell types were tested with comprehensive and quantitative assays capable of detecting low-percentage NFI mutations. This approach confirmed the biallelic NF1 inactivation in Schwann cells in neurofibromas and, for the first time, demonstrated biallelic NF1 inactivation in melanocytes in NF1-related cafe-au-lait macules. Interestingly, both disease features arise even within a background of predominantly NF1 wild-type cells. Together, the data provide molecular evidence that (1) the distinct clinical picture of the patients is due to mosaicism for the NF1 mutation and (2) the mosaic phenotype reflects the embryonic timing and, accordingly, the neural crest-derived cell type involved in the somatic W I mutation. The study of the affected cell types provides important insight into developmental concepts underlying particular NF1-related disease features and opens avenues for improved diagnosis and genetic counseling of individuals with mosaic NFI.