| Germline KRAS mutations cause Noonan syndrome. | |
| | |
MedLine Citation:
|
PMID: 16474405 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Suzanne Schubbert; Martin Zenker; Sara L Rowe; Silke Böll; Cornelia Klein; Gideon Bollag; Ineke van der Burgt; Luciana Musante; Vera Kalscheuer; Lars-Erik Wehner; Hoa Nguyen; Brian West; Kam Y J Zhang; Erik Sistermans; Anita Rauch; Charlotte M Niemeyer; Kevin Shannon; Christian P Kratz |
Related Documents
:
|
16007675 - Neuropathic scapuloperoneal syndrome (davidenkow's syndrome) with chromosome 17p11.2 de... 20636395 - Can a familial gastrointestinal tumour syndrome be allelic with waardenburg syndrome? 18572195 - Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). 15293285 - Chorein detection for the diagnosis of chorea-acanthocytosis. 9438265 - Salivary cortisol profiles in chronic fatigue syndrome. 641945 - Recessively inherited costovertebral segmentation defect with mesomelia and peculiar fa... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-02-12 |
Journal Detail:
|
Title: Nature genetics Volume: 38 ISSN: 1061-4036 ISO Abbreviation: Nat. Genet. Publication Date: 2006 Mar |
Date Detail:
|
Created Date: 2006-02-27 Completed Date: 2006-05-02 Revised Date: 2007-11-15 |
Medline Journal Info:
|
Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: United States |
Other Details:
|
Languages: eng Pagination: 331-6 Citation Subset: IM |
Affiliation:
|
Department of Pediatrics, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
|
OMIM/115150; 163950 |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adolescent Female Genes, ras* Germ-Line Mutation* Guanosine Triphosphate / metabolism Heterozygote Detection Humans Infant Intracellular Signaling Peptides and Proteins / genetics Male Noonan Syndrome / genetics* Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatases / genetics |
| Grant Support | |
ID/Acronym/Agency:
|
R01 CA104282/CA/NCI NIH HHS; R01 CA72614/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Intracellular Signaling Peptides and Proteins; 86-01-1/Guanosine Triphosphate; EC 3.1.3.48/PTPN11 protein, human; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.1.3.48/Protein Tyrosine Phosphatases |
| Comments/Corrections | |
Erratum In:
|
Nat Genet. 2006 May;38(5):598 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.
Next Document: Feedback repression is required for mammalian circadian clock function.