1. Germline BRAF Mutations in Noonan, LEOPARD, and Cardiofaciocutaneous Syndromes: Molecular Diversity and Associated Phenotypic Spectrum
- Author
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Efisio Puxeddu, Giorgia Esposito, Angelo Selicorni, Cesare Rossi, Anna Sarkozy, Sonia Moretti, Maria Lisa Dentici, Marco Tartaglia, Grazia M.S. Mancini, Bruno Dallapiccola, Francesca Pantaleoni, Margherita Silengo, Viviana Cordeddu, Maria Cristina Digilio, Laura Mazzanti, Anna Paola Scioletti, Franco Stanzial, Luigi Memo, Bruno Marino, Giovanni Battista Ferrero, Francesca Faravelli, Claudio Carta, Giuseppe Zampino, Francesca Romana Lepri, Bruce D. Gelb, Valentina Petrangeli, Liborio Stuppia, Clinical Genetics, A. Sarkozy, C. Carta, S. Moretti, G. Zampino, M.C. Digilio, F. Pantaleoni, A.P. Scioletti, G. Esposito, V. Cordeddu, F. Lepri, V. Petrangeli, M.L. Dentici, G.M. Mancini, A. Selicorni, C. Rossi, L. Mazzanti, B. Marino, G:B. Ferrero, M.C. Silengo, L. Memo, F. Stanzial, F. Faravelli, L. Stuppia, E. Puxeddu, B.D. Gelb, B. Dallapiccola, and M. Tartaglia.
- Subjects
Heart Defects, Congenital ,Male ,Proto-Oncogene Proteins B-raf ,Genotype ,NOONAN, LEOPARD AND CARDIOFACIOCUTANEOUS SYNDROMES ,Mutation, Missense ,Biology ,RASopathy ,genotype-phenotype correlation ,Cardiofaciocutaneous syndrome ,LEOPARD Syndrome ,Article ,Germline ,Noonan syndrome ,Leopard syndrome ,BRAF ,Mutation ,Cohort Studies ,Germline mutation ,Gene Frequency ,SDG 3 - Good Health and Well-being ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Germ-Line Mutation ,Genetics (clinical) ,mutation analysis ,braf ,cardiofaciocutaneous syndrome ,cfcs ,functional studies ,leopard syndrome ,noonan syndrome ,LEOPARD syndrome ,CFCS ,Genetic Variation ,medicine.disease ,PTPN11 ,Phenotype ,BRAF MUTATIONS ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,LEOPARD AND CARDIOFACIOCUTANEOUS SYNDROMES ,Face ,Skin Abnormalities ,NOONAN ,Female ,Noonan Syndrome with Multiple Lentigines - Abstract
Noonan, LEOPARD, and cardiofaciocutaneous Syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS-mitogen-activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N = 270), LS (N = 6), and CFCS (N = 33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (5296), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer-associated defects. NS-causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer-associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions. Hum Mutat 30, 695-702, 2009. (C) 2009 Wiley-Liss, Inc.
- Published
- 2009