PDF(Pubmed)
Abstract：
Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy.
摘要：
CasitasB系淋巴瘤（CBL）编码具有E3连接酶活性的接头蛋白，该接头蛋白负控制受体酪氨酸激酶下游的细胞内信号传导。体细胞CBL突变在多种癌症中起驱动作用，特别是骨髓性恶性肿瘤，而同一基因中的种系缺陷是与Noonan综合征（NS）临床重叠并易患幼年型粒单核细胞白血病和血管炎的RAS病的基础。该疾病的其他特征包括心脏缺陷，产后生长延迟，隐睾,面部畸形，和发展自身免疫性疾病的倾向。在这里，我们报告了一个新的CBL变体（c.1202G>T;p.Cys401Phe），从头出现在一个有caféau-lait黄斑的受试者中，喂养困难，轻度畸形特征，精神运动延迟，自闭症谱系障碍，血小板减少症,肝脾肿大,和复发性高转氨酶血症。识别的变体影响位于RING指结构域中的进化保守残基，种系和体细胞突变的已知突变热点。功能研究表明，在瞬时转染的COS1细胞中，EGF诱导的ERK磷酸化增强。目前的发现进一步支持致病性CBL变体与免疫学和血液学表现的关联，在表现的背景下，只有轻微的发现让人想起NS或临床相关的RAS病。
