期刊
HUMAN MUTATION
卷 32, 期 1, 页码 33-43出版社
WILEY
DOI: 10.1002/humu.21377
关键词
Noonan syndrome; NS; gain of function; GAP resistance; KRAS; Ras isoforms; Ras mutations
资金
- German Research Foundation [DFG AH 92/5-1]
- German Ministry of Science and Education (BMBF) [01GS08100]
- Research Committee of the Medical Faculty of the Heinrich-Heine University Dusseldorf
- Max-Planck Society
- E-Rare project NSEuroNet
The KRAS gene is the most common locus for somatic gain-of-function mutations in human cancer. Germline KRAS mutations were shown recently to be associated with developmental disorders, including Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFCS), and Costello syndrome (CS). The molecular basis of this broad phenotypic variability has in part remained elusive so far. Here, we comprehensively analyzed the biochemical and structural features of ten germline KRAS mutations using physical and cellular biochemistry. According to their distinct biochemical and structural alterations, the mutants can be grouped into five distinct classes, four of which markedly differ from RAS oncoproteins. Investigated functional alterations comprise the enhancement of intrinsic and guanine nucleotide exchange factor (GEF) catalyzed nucleotide exchange, which is alternatively accompanied by an impaired GTPase-activating protein (GAP) stimulated GTP hydrolysis, an overall loss of functional properties, and a deficiency in effector interaction. In conclusion, our data underscore the important role of RAS in the pathogenesis of the group of related disorders including NS, CFCS, and CS, and provide clues to the high phenotypic variability of patients with germline KRAS mutations. Hum Mutat 32:33-43, 2011. (C) 2010 Wiley-Liss, Inc.
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