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PMID:22302539

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Citation

Razzaque, MA, Komoike, Y, Nishizawa, T, Inai, K, Furutani, M, Higashinakagawa, T and Matsuoka, R (2012) Characterization of a novel KRAS mutation identified in Noonan syndrome. Am. J. Med. Genet. A 158A:524-32

Abstract

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.

Links

PubMed Online version:10.1002/ajmg.a.34419

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A2R8Q8S1

involved_in

GO:0007507: heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120911-3

P

Seeded From UniProt

complete

DANRE:A0A2R8Q8S1

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120911-3

P

Seeded From UniProt

complete

DANRE:Q6AZA4

involved_in

GO:0007507: heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120911-3

P

Seeded From UniProt

complete

DANRE:Q6AZA4

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120911-3

P

Seeded From UniProt

complete


See also

References

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