Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype

Claudio Carta, Francesca Pantaleoni, Gianfranco Bocchinfuso, Lorenzo Stella, Isabella Vasta, Anna Sarkozy, Cristina Digilio, Antonio Palleschi, Antonio Pizzuti, Paola Grammatico, Giuseppe Zampino, Bruno Dallapiccola, Bruce D. Gelb, Marco Tartaglia

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)129-135
Number of pages7
JournalAmerican Journal of Human Genetics
Volume79
Issue number1
DOIs
Publication statusPublished - Jul 2006

ASJC Scopus subject areas

  • Genetics

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