Germline KRAS mutations cause Noonan syndrome.
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.
Department of Pediatrics, University of California, 513 Parnassus Avenue, San Francisco, California 94143, USA.
Suzanne
S
Schubbert
Martin
M
Zenker
Sara L
SL
Rowe
Silke
S
Böll
Cornelia
C
Klein
Gideon
G
Bollag
Ineke
I
van der Burgt
Luciana
L
Musante
Vera
V
Kalscheuer
Lars-Erik
LE
Wehner
Hoa
H
Nguyen
Brian
B
West
Kam Y J
KY
Zhang
Erik
E
Sistermans
Anita
A
Rauch
Charlotte M
CM
Niemeyer
Kevin
K
Shannon
Christian P
CP
Kratz
D000293:Adolescent; D005260:Female; D011905:Genes, ras; D006580:Genetic Carrier Screening; D018095:Germ-Line Mutation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D009634:Noonan Syndrome / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D006160:Guanosine Triphosphate; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases