Biochemistry, Cellular and Molecular Biology Program, Johns Hopkins School of Medicine, and Department of Neurology and Developmental Medicine, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
N Engl J Med. 2013 May 23;368(21):1971-9. doi: 10.1056/NEJMoa1213507. Epub 2013 May 8.
The Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge-Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified.
We performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge-Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge-Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay.
We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Gαq.
The Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis. (Funded by the National Institutes of Health and Hunter's Dream for a Cure Foundation.).
Sturge-Weber 综合征是一种散发性先天性神经皮肤疾病，其特征为眼部三叉神经分支分布区的葡萄酒色斑、脑软脑膜和脉络丛的异常毛细血管静脉血管、青光眼、癫痫发作、中风和智力障碍。据推测，体细胞镶嵌突变破坏血管发育会导致 Sturge-Weber 综合征和葡萄酒色斑，并且表现的严重程度和范围取决于突变发生的发育时间点。迄今为止，尚未发现此类突变。
我们对 3 名 Sturge-Weber 综合征患者的明显受影响组织和正常组织进行了全基因组测序。我们使用扩增子测序和 SNaPshot 检测，对 50 名 Sturge-Weber 综合征患者、葡萄酒色斑患者或两者均无（对照组）的 97 个样本进行了体细胞镶嵌突变的检测，并使用相关效应物的磷酸化特异性抗体和荧光素酶报告基因检测，研究了突变对下游信号的影响。
我们在 26 名 Sturge-Weber 综合征患者中有 23 名（88%）和 13 名无综合征性葡萄酒色斑患者中有 12 名（92%）的受影响组织样本中发现了 GNAQ 中的非同义单核苷酸变异（c.548G→A，p.Arg183Gln），但在 4 名患有无关脑血管畸形的患者的任何受影响组织样本或 6 名对照组的任何样本中均未发现。突变等位基因在受影响组织中的流行率范围为 1.0%至 18.1%。在突变 Gαq 的转基因表达过程中，细胞外信号调节激酶的活性略有增加。
Sturge-Weber 综合征和葡萄酒色斑是由 GNAQ 中的体细胞激活突变引起的。这一发现证实了一个长期存在的假说。（由美国国立卫生研究院和 Hunter's Dream for a Cure 基金会资助）。
