Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype
Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype
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DOI：
10.1016/j.ajhg.2010.06.015
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发表时间：
2010-08-13
影响因子：
9.8
通讯作者：
Tartaglia, Marco
中科院分区：
文献类型：
--
作者：
Martinelli, Simone;De Luca, Alessandro;Tartaglia, Marco
RAS信号在控制细胞对细胞外刺激的适当反应中起关键作用，并参与早期和晚期发育过程。虽然通过该途径的增强流动已被确定为肿瘤发生的主要贡献者，但最近的发现表明，异常RAS激活导致一组临床相关的发育障碍，其特征在于面部畸形、广泛的心脏病、生长减缓、可变的认知缺陷、外胚层和肌肉骨骼异常以及某些恶性肿瘤的风险增加。在这里，我们报告说，杂合子种系突变CBL，一种肿瘤抑制基因，突变的骨髓恶性肿瘤和编码多价接头蛋白与E3泛素连接酶活性，可以根据临床特征拟合或部分重叠努南综合征（NS），最常见的条件下，这种疾病的家庭的表型。独立的CBL突变被确定在两个散发病例和两个家庭中的365个无关的受试者有NS或提示功能，并在以前确定的疾病基因突变阴性。记录表型异质性和可变表达性。突变是改变位于RING指结构域或连接该结构域与N-末端酪氨酸激酶结合结构域（骨髓恶性肿瘤中已知的突变热点）的接头中的进化保守残基的错义变化。突变显示影响CBL介导的受体泛素化和通过RAS的信号流失调。这些发现证明CBL中的生殖系突变改变了发育，导致类似NS的临床可变条件，并可能易患恶性肿瘤。
RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies.