Characterization of a novel KRAS mutation identified in Noonan syndrome
- Authors
- Razzaque, M.A., Komoike, Y., Nishizawa, T., Inai, K., Furutani, M., Higashinakagawa, T., and Matsuoka, R.
- ID
- ZDB-PUB-120207-4
- Date
- 2012
- Source
- American journal of medical genetics. Part A 158A(3): 524-532 (Journal)
- Registered Authors
- Keywords
- Noonan syndrome, congenital heart disease, KRAS, MAPK signaling, maldevelopment, RAS, RASopathy
- MeSH Terms
-
- Amino Acid Sequence
- Amino Acid Substitution
- Animals
- Cohort Studies
- Female
- Gene Knockdown Techniques
- Genes, ras*
- Humans
- In Situ Hybridization
- Male
- Mice
- Molecular Sequence Data
- Mutation*
- Noonan Syndrome/genetics*
- Pedigree
- Sequence Homology, Amino Acid
- Zebrafish
- PubMed
- 22302539 Full text @ Am. J. Med. Genet. A
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.