Characterization of a novel KRAS mutation identified in Noonan syndrome.
Noonan syndrome (NS) is the most common non-chromosomal syndrome seen in children and is characterized by short stature, dysmorphic facial features, chest deformity, a wide range of congenital heart defects and developmental delay of variable degree. Mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathways cause about 70% of NS cases with a KRAS mutation present in about 2%. In a cohort of 65 clinically confirmed NS patients of Japanese origin, we screened for mutations in the RAS genes by direct sequencing. We found a novel mutation in KRAS with an amino acid substitution of asparagine to serine at codon 116 (N116S). We analyzed the biological activity of this mutant by ectopic expression of wild-type or mutant KRAS. NS-associated KRAS mutation resulted in Erk activation and active Ras-GTP levels, and exhibited mild cell proliferation. In addition, kras-targeted morpholino knocked-down zebrafish embryos caused heart and craniofacial malformations, while the expression of mutated kras resulted in maldevelopment of the heart. Our findings implicate that N116S change in KRAS is a hyperactive mutation which is a causative agent of NS through maldevelopment of the heart.
International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, Tokyo, Japan.
Md Abdur
MA
Razzaque
Yuta
Y
Komoike
Tsutomu
T
Nishizawa
Kei
K
Inai
Michiko
M
Furutani
Toru
T
Higashinakagawa
Rumiko
R
Matsuoka
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015331:Cohort Studies; D005260:Female; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish