RESUMO
Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause approximately 60% of cases of Noonan syndrome. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome-associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.
Assuntos
Mutação de Sentido Incorreto , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Animais , Linhagem Celular , Linhagem Celular Transformada , Feminino , Coração/embriologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miocárdio/metabolismo , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-raf/química , Proteínas Proto-Oncogênicas c-raf/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
PURPOSE: To identify the relationship between specific genes and phenotypic features of Williams syndrome. METHODS: Subjects were selected based on their deletion status determined by fluorescence in situ hybridization using a panel of 24 BACs and cosmids spanning the region commonly deleted and single gene analysis using Southern blotting. From the cohort of subjects, three had atypical deletions. Physical examinations and cognitive tests were administered to the three subjects and the results were compared to those from a cohort of typical WS subjects. RESULTS: The molecular results indicate smaller deletions for each subject. In all three cases, typical Williams facies were absent and visual spatial abilities were above that of full deletion WS subjects, particularly in the qualitative aspects of visual spatial processing. CONCLUSIONS: Combining the molecular analysis with the cognitive results suggest that the genes GTF2IRD1 and GTF2I contribute to deficits on visual spatial functioning.
Assuntos
Cromossomos Humanos Par 7 , Proteínas Musculares/genética , Proteínas Nucleares/genética , Transativadores/genética , Fatores de Transcrição TFII/genética , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico , Estudos de Coortes , Cosmídeos , Feminino , Deleção de Genes , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Testes de Inteligência , Modelos Genéticos , Fenótipo , Mapeamento Físico do Cromossomo , Síndrome de Williams/patologiaRESUMO
OBJECTIVES: The purpose of this study was to determine the feasibility of coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) in children with Kawasaki disease (KD). BACKGROUND: Doppler-derived CFVR is a reliable marker predicting the presence of myocardial ischemia. METHODS: We studied 49 patients (median age 11 years) with KD. The CFVR was calculated as the ratio of hyperemic to basal peak (peak CFVR) and mean (mean CFVR) diastolic flow velocities in the posterior descending coronary artery (PD) and left anterior descending coronary artery (LAD). The CFVR measurements by TTDE were compared with the results of coronary angiography, thallium-201 (Tl-201) single-photon emission computed tomography (SPECT), and intracoronary Doppler study. RESULTS: The CFVR measurements by TTDE were obtained in 92 (94%) of 98 vessels of the PD and LAD in 49 study patients. Both peak and mean CFVRs for 21 stenotic vessels were significantly smaller than those for 35 normal vessels and for 20 vessels with aneurysmal lesions (p < 0.0001). Peak and mean CFVR <2.0 predicted significant coronary stenosis, as determined by coronary angiography, with sensitivities and specificities of 89% and 96% and 89% and 97%, respectively. Also, both peak and mean CFVRs were correlated with reversible perfusion defects on Tl-201 SPECT (agreement 80%; kappa 0.4). The correlation between peak and mean CFVRs determined by the TTDE and intracoronary Doppler studies in 36 vessels of 23 patients were 0.76 and 0.80, respectively. CONCLUSIONS: The CFVR measured by TTDE predicts the presence of significant coronary stenosis of either the right coronary artery or LAD, as well as myocardial ischemia of these territories in children with KD.