Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.
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.
Gremer
Lothar
L
Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University, Düsseldorf, Germany.
Merbitz-Zahradnik
Torsten
T
Dvorsky
Radovan
R
Cirstea
Ion C
IC
Kratz
Christian Peter
CP
Zenker
Martin
M
Wittinghofer
Alfred
A
Ahmadian
Mohammad Reza
MR
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002658:Developmental Disabilities / Q000235:genetics*; D004476:Ectodermal Dysplasia / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009634:Noonan Syndrome / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
D020690:GTPase-Activating Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins