Greenwood Genetic Center, Greenwood, SC 29646, USA.
Clin Genet. 2011 May;79(5):468-74. doi: 10.1111/j.1399-0004.2010.01495.x.
BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio-facio-cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild-type BRAF but is less strongly activating than the cancer-associated p.V600E mutation.
BRAF 是 BRAF 蛋白的产物，是一种丝氨酸/苏氨酸蛋白激酶，也是 Ras 的直接下游效应物之一。BRAF 中的体细胞突变发生在许多人类癌症中，而种系 BRAF 突变则导致心面多发痣综合征（cardio-facio-cutaneous，CFC）。一种反复出现的体细胞突变 p.V600E 常见于多种肿瘤类型，如黑色素瘤、甲状腺乳头状癌、结肠癌和卵巢癌。然而，影响密码子 600 的种系突变从未被描述过。在这里，我们报告了一例 CFC 综合征患者，存在 BRAF 第 600 密码子的新生种系突变，这首次提供了证据表明，涉及这一关键密码子的致病性种系突变不仅与发育相容，而且还可导致 CFC 表型。体外功能分析表明，与野生型 BRAF 相比，该突变（即第 600 密码子的缬氨酸被甘氨酸取代，p.V600G）导致 ERK 和 ELK 磷酸化增加，但比与癌症相关的 p.V600E 突变的激活程度低。
