Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi
Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi
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DOI：
10.1172/jci28163
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发表时间：
2006-08-01
影响因子：
15.9
通讯作者：
Hartmann, Arndt
中科院分区：
文献类型：
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作者：
Hafner, Christian;van Oers, Johanna M. M.;Hartmann, Arndt
表皮痣是一种常见的先天性皮肤病变，发病率为千分之一；然而，它们的遗传基础仍然难以捉摸。FGF受体3 （FGFR3）的种系突变可引起常染色体显性骨骼疾病，如软骨发育不全和脂肪增生性发育不良，这可能与皮肤黑棘皮病有关。黑棘皮病与非类器官、非表皮松解型的普通表皮痣具有一些临床和组织学特征。我们使用SNaPshot多重试验筛选了33例患者的39个表皮痣，其中11个激活FGFR3点突变。此外，FGFR3的外显子19被直接测序。我们在33例非类器官、非表皮松解性表皮痣患者中的11例（33%）中发现了激活FGFR3突变，几乎完全位于密码子248 （R248C）。在其中4例病例中，可以分析邻近组织学正常皮肤的样本，发现没有FGFR3突变。我们的研究结果表明，很大一部分表皮痣是由激活人类表皮中FGFR3突变的嵌合素引起的，继发于早期胚胎发育中的合子后突变。R248C突变似乎是表皮痣中FGFR3突变的热点。
Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acanthosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepidermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicisin of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi.