A restricted spectrum of NRAS mutations causes Noonan syndrome

• Published in: Nature genetics Vol. 42; no. 1; pp. 27 - 29
• Main Authors: Gelb, Bruce D, Gremer, Lothar, Digilio, Cristina, Dentici, Maria L, Roberts, Amy E, Zampino, Giuseppe, Kratz, Christian P, Dallapiccola, Bruno, Mazzanti, Laura, Stuppia, Liborio, Pantaleoni, Francesca, Ahmadian, Mohammad R, Zenker, Martin, Lepri, Francesca, Kutsche, Kerstin, Silengo, Margherita Cirillo, Joshi, Victoria A, König, Rainer, Carta, Claudio, Horn, Denise, Merbitz-Zahradnik, Torsten, Pennacchio, Len A, Mundlos, Stefan, Tartaglia, Marco, Dvorsky, Radovan, Wittinghofer, Alfred, Cirstea, Ion C, Seemanova, Eva, Patton, Michael A, Rossi, Cesare, Kucherlapati, Raju S
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing Group 01.01.2010
• Subjects: Adolescent; Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Child; Child, Preschool; Chlorocebus aethiops; COS Cells; Crystal structure; Diseases of the osteoarticular system; DNA Mutational Analysis; Female; Fundamental and applied biological sciences. Psychology; G proteins; Gene mutations; Genes, ras; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Humans; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Middle Aged; Mitogen-Activated Protein Kinases - metabolism; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Mutation; Noonan syndrome; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Noonan Syndrome - pathology; Phosphorylation; Physiological aspects; Protein Structure, Tertiary; Proteins; ras Proteins - chemistry; ras Proteins - genetics; Risk factors; Sequence Homology, Amino Acid; Signal transduction; Studies; Transfection; Young Adult; Germany; Nervous system diseases; Noonan syndrome; Diseases of the osteoarticular system; Cardiovascular disease; Mutation; Onc gene; Osteochondrodysplasia; Genetic disease; Spectrum
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.497

Noonan syndrome, a developmental disorder characterized by congenital heart defects, reduced growth, facial dysmorphism and variable cognitive deficits, is caused by constitutional dysregulation of the RAS-MAPK signaling pathway. Here we report that germline NRAS mutations conferring enhanced stimulus-dependent MAPK activation account for some cases of this disorder. These findings provide evidence for an obligate dependency on proper NRAS function in human development and growth.