Germline KRAS mutations cause Noonan syndrome

Suzanne Schubbert¹, Martin Zenker², Sara L Rowe¹, Silke Böll³, Cornelia Klein³, Gideon Bollag⁴, Ineke van der Burgt⁵, Luciana Musante⁶, Vera Kalscheuer⁶, Lars-Erik Wehner⁷, Hoa Nguyen⁴, Brian West⁴, Kam Y J Zhang⁴, Erik Sistermans⁵, Anita Rauch², Charlotte M Niemeyer³, Kevin Shannon^1, 8 & Christian P Kratz³

¹  Department of Pediatrics, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA.

²  Institute of Human Genetics, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.

³  Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany.

⁴  Plexxikon, Inc., 91 Bolivar Dr., Berkeley, California 94710, USA.

⁵  Department of Human Genetics, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands.

⁶  Max Planck Institute of Molecular Genetics, 14195 Berlin, Germany.

⁷  Institute of Human Genetics, University of Göttingen, 37075 Germany.

⁸  Comprehensive Cancer Center, University of California, San Francisco, California 94115, USA.

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects¹. Heterozygous mutations in PTPN11, which encodes SHP-2, cause 50% of cases of Noonan syndrome^{1, 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 syndrome^{1, 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.

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