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.

• MeSH
• genetická predispozice k nemoci MeSH
• juvenilní myelomonocytární leukemie komplikace   genetika   MeSH
• kojenec MeSH
• kryptorchismus komplikace   genetika   MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny c-cbl genetika   fyziologie   MeSH
• rodokmen MeSH
• vývojové poruchy u dětí komplikace   genetika   MeSH
• zárodečné mutace * fyziologie   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• CBL protein, human MeSH Prohlížeč
• protoonkogenní proteiny c-cbl MeSH