Germline Missense Mutations Affecting KRAS Isoform B Are Associated with a Severe Noonan Syndrome Phenotype

• Published in: American journal of human genetics Vol. 79; no. 1; pp. 129 - 135
• Main Authors: Carta, Claudio, Pantaleoni, Francesca, Bocchinfuso, Gianfranco, Stella, Lorenzo, Vasta, Isabella, Sarkozy, Anna, Digilio, Cristina, Palleschi, Antonio, Pizzuti, Antonio, Grammatico, Paola, Zampino, Giuseppe, Dallapiccola, Bruno, Gelb, Bruce D., Tartaglia, Marco
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.07.2006; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Base Sequence; Biological and medical sciences; Diseases of the osteoarticular system; DNA Primers; General aspects. Genetic counseling; Genes; Genes, ras; Genetic disorders; Genotype & phenotype; Germ-Line Mutation; Humans; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Models, Molecular; Molecular Sequence Data; Mutation; Mutation, Missense; Noonan Syndrome - genetics; Phenotype; Proteins; Human; Nervous system diseases; Diseases of the osteoarticular system; Cardiovascular disease; Genetic disease; K ras Gene; Phenotype; Association; Missense mutation; Germ line; Noonan syndrome; Genetics; Severe; Osteochondrodysplasia
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/504394

Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart disease, and multiple skeletal and hematologic defects. NS is an autosomal dominant trait and is genetically heterogeneous. Gain of function of SHP-2, a protein tyrosine phosphatase that positively modulates RAS signaling, is observed in nearly 50% of affected individuals. Here, we report the identification of heterozygous KRAS gene mutations in two subjects exhibiting a severe NS phenotype with features overlapping those of cardiofaciocutaneous and Costello syndromes. Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions (Val152Gly and Asp153Val) perturb the conformation of the guanine ring–binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor.