Dataset Information

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

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 (52%), 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.

SUBMITTER: Sarkozy A

PROVIDER: S-EPMC4028130 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

Sarkozy Anna A Carta Claudio C Moretti Sonia S Zampino Giuseppe G Digilio Maria C MC Pantaleoni Francesca F Scioletti Anna Paola AP Esposito Giorgia G Cordeddu Viviana V Lepri Francesca F Petrangeli Valentina V Dentici Maria L ML Mancini Grazia M S GM Selicorni Angelo A Rossi Cesare C Mazzanti Laura L Marino Bruno B Ferrero Giovanni B GB Silengo Margherita Cirillo MC Memo Luigi L Stanzial Franco F Faravelli Francesca F Stuppia Liborio L Puxeddu Efisio E Gelb Bruce D BD Dallapiccola Bruno B Tartaglia Marco M

Human mutation 20090401 4

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 g ...[more]

PMID: 19206169

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Project description:Noonan and LEOPARD syndromes (NS and LS) belong to a group of related disorders called RASopathies characterized by abnormalities of multiple organs and systems including hypertrophic cardiomyopathy and dysmorphic facial features. There are no approved drugs for these two rare diseases, but it is known that a missense mutation in PTPN11 genes is associated with approximately 50% and 70% of NS and LS cases, respectively. In this study, we implemented a hybrid computational drug repositioning framework by integrating transcriptomic and structure-based approaches to explore potential treatment options for NS and LS. Specifically, disease signatures were derived from the transcriptomic profiles of human induced pluripotent stem cells (iPSCs) from NS and LS patients and reverse correlated to drug transcriptomic signatures from CMap and L1000 projects on the basis that if disease and drug transcriptomic signatures are reversely correlated, the drug has the potential to treat that disease. The compounds that were ranked top based on their transcriptomic profiles were docked to mutated and wild-type 3D structures of PTPN11 by an adjusted Induced Fit Docking (IFD) protocol. In addition, we prioritized repositioned candidates for NS and LS by a consensus ranking strategy. Network analysis and phenotypic anchoring of the transcriptomic data could discriminate the two diseases at the molecular level. Furthermore, the adjusted IFD protocol was able to recapitulate the binding specificity of potential drug candidates to mutated 3D structures, revealing the relevant amino acids. Importantly, a list of potential drug candidates for repositioning was identified including 61 for NS and 43 for LS and was further verified from literature reports and on-going clinical trials. Altogether, this hybrid computational drug repositioning approach has highlighted a number of drug candidates for NS and LS and could be applied to identifying drug candidates for other diseases as well.

Dataset Information

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

Publications

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

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