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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 307757.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Germline KRAS mutations cause Noonan syndrome
Authors:Schubbert, Suzanne; Zenker, Martin; Rowe, Sara L .; Böll, Silke; Klein, Cornelia; Bollag, Gideon; van der Burgt, Ineke; Musante, Luciana; Kalscheuer, Vera M.; Wehner, Lars-Erik; Nguyen, Hoa; West, Brian; Zhang, Kam Y. J.; Sistermans, Erik; Rauch, Anita; Niemeyer, Charlotte M.; Shannon, Kevin; Kratz, Christian P.
Date of Publication (YYYY-MM-DD):2006-02-12
Title of Journal:Nature Genetics
Journal Abbrev.:Nat. Genet.
Issue / Number:3
Start Page:331
End Page:336
Copyright:©2006 Nature Publishing Group
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Comment of the Author/Creator:Correspondence should be addressed to Christian P Kratz christian.kratz@uniklinik-freiburg.de or Kevin Shannon shannonk@peds.ucsf.edu

There is an Corrigendum (May 2006) associated with this Letter.
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations: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.Institute of Human Genetics, University of Göttingen, 37075 Germany;
7.Comprehensive Cancer Center, University of California, San Francisco, California 94115, USA.
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