| Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. | |
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MedLine Citation:
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PMID: 20694012 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Charlotte M Niemeyer; Michelle W Kang; Danielle H Shin; Ingrid Furlan; Miriam Erlacher; Nancy J Bunin; Severa Bunda; Jerry Z Finklestein; Kathleen M Sakamoto; Thomas A Gorr; Parinda Mehta; Irene Schmid; Gabriele Kropshofer; Selim Corbacioglu; Peter J Lang; Christoph Klein; Paul-Gerhard Schlegel; Andrea Heinzmann; Michaela Schneider; Jan Starý; Marry M van den Heuvel-Eibrink; Henrik Hasle; Franco Locatelli; Debbie Sakai; Sophie Archambeault; Leslie Chen; Ryan C Russell; Stephanie S Sybingco; Michael Ohh; Benjamin S Braun; Christian Flotho; Mignon L Loh |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-08 |
Journal Detail:
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Title: Nature genetics Volume: 42 ISSN: 1546-1718 ISO Abbreviation: Nat. Genet. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-30 Completed Date: 2010-09-17 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: United States |
Other Details:
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Languages: eng Pagination: 794-800 Citation Subset: IM |
Affiliation:
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Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany. charlotte.niemeyer@uniklinik-freiburg.de |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Child, Preschool Cryptorchidism / complications, genetics DNA Mutational Analysis Developmental Disabilities / complications, genetics* Female Genetic Predisposition to Disease Germ-Line Mutation* / physiology Humans Infant Infant, Newborn Leukemia, Myelomonocytic, Juvenile / complications, genetics* Male Pedigree Proto-Oncogene Proteins c-cbl / genetics*, physiology |
| Grant Support | |
ID/Acronym/Agency:
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CA113557/CA/NCI NIH HHS; K08 CA103868/CA/NCI NIH HHS; R01 CA104282/CA/NCI NIH HHS; T32GM007618/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 6.3.2.-/CBL protein, human; EC 6.3.2.-/Proto-Oncogene Proteins c-cbl |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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