Pawlikowski Jeffrey S, Brock Claire, Chen Sheau-Chiann, Al-Olabi Lara, Nixon Colin, McGregor Fiona, Paine Simon, Chanudet Estelle, Lambie Wendy, Holmes William M, Mullin James M, Richmond Ann, Wu Hong, Blyth Karen, King Ayala, Kinsler Veronica A, Adams Peter D
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK; Current address: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; Beatson Institute for Cancer Research, Glasgow, UK.
J Invest Dermatol. 2015 Aug;135(8):2093-2101. doi: 10.1038/jid.2015.114. Epub 2015 Mar 27.
Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.
先天性黑素细胞痣（CMN）综合征是色素性黑素细胞痣与皮肤外特征的关联，典型表现为中枢神经系统内的黑素细胞，最常见的原因是NRAS密码子61突变。这种疾病目前无法治疗，皮肤、脑或软脑膜发生黑色素瘤的风险很高。我们之前提出Wnt信号在黑素细胞痣形成中起关键作用，这表明激活的Wnt信号在CMN综合征的发病机制中可能与激活的NRAS协同作用。一些家族易感性表明种系因素对CMN综合征有影响，具有相似皮肤表型的个体中神经学表型的变异性也是如此。因此，我们对CMN患者的种系DNA进行了外显子组测序，以揭示罕见或未描述的Wnt信号改变。在黑素细胞中携带激活的NRAS（Q61K）和Wnt信号的小鼠模型表现出CMN综合征的显著特征，尤其是神经受累。在这种疾病的首个治疗模型中，通过产后急性给予MEK抑制剂，这些先天性且之前被认为是永久性的特征得到了显著抑制。这些数据表明激活的NRAS和异常的Wnt信号共同作用导致CMN综合征。产后MEK抑制是这种使人衰弱疾病患者的一种潜在候选治疗方法。
