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Germline KRAS mutations cause Noonan syndrome

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50439

Musante,  Luciana
Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50369

Kalscheuer,  Vera M.
Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Zitation

Schubbert, S., Zenker, M., Rowe, S. L.., Böll, S., Klein, C., Bollag, G., et al. (2006). Germline KRAS mutations cause Noonan syndrome. Nature Genetics, 38(3), 331-336. doi:10.1038/ng1748.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-8495-1
Zusammenfassung
Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects1. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approx50% of cases of Noonan syndrome1, 2. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras3. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome1, 4. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage–specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.