Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
Nat Genet. 2010 Sep;42(9):794-800. doi: 10.1038/ng.641. Epub 2010 Aug 8.
CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.
CBL 编码 Cbl 蛋白家族的成员，作为一种 E3 泛素连接酶发挥作用。我们描述了一种源自种系错义 CBL 突变的显性发育障碍，其特征为生长受损、发育迟缓、隐睾和易患少年型粒单核细胞白血病（JMML）。一些个体经历了 JMML 的自发消退，但在以后的生活中发展为血管炎。重要的是，受影响儿童的 JMML 标本通过后天等基因获得性缺失正常的 CBL 等位基因。与这些遗传数据一致，常见的 p.371Y>H 改变的 Cbl 蛋白仅在造血细胞中诱导细胞因子非依赖性生长和 ERK、AKT 和 S6 的组成性磷酸化，在这些细胞中，正常 Cbl 表达通过 RNA 干扰降低。我们得出结论，种系 CBL 突变具有发育、肿瘤发生和功能后果，类似于由高活性 Ras/Raf/MEK/ERK 信号引起的疾病，包括神经纤维瘤病 1 型、Noonan 综合征、Costello 综合征、心面脂体综合征和 Legius 综合征。
