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Germline KRAS mutations cause Noonan syndrome 总被引:22,自引:0,他引:22
Schubbert S Zenker M Rowe SL Böll S Klein C Bollag G van der Burgt I Musante L Kalscheuer V Wehner LE Nguyen H West B Zhang KY Sistermans E Rauch A Niemeyer CM Shannon K Kratz CP 《Nature genetics》2006,38(3):331-336
Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. 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 syndrome. 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. 相似文献
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Koolen DA Vissers LE Pfundt R de Leeuw N Knight SJ Regan R Kooy RF Reyniers E Romano C Fichera M Schinzel A Baumer A Anderlid BM Schoumans J Knoers NV van Kessel AG Sistermans EA Veltman JA Brunner HG de Vries BB 《Nature genetics》2006,38(9):999-1001
Submicroscopic genomic copy number changes have been identified only recently as an important cause of mental retardation. We describe the detection of three interstitial, overlapping 17q21.31 microdeletions in a cohort of 1,200 mentally retarded individuals associated with a clearly recognizable clinical phenotype of mental retardation, hypotonia and a characteristic face. The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism. 相似文献
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