GermlineBRAFmutations 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 5 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 than 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.

Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

“…Pulmonic stenosis is commonly observed among individuals with mutations in the PTPN11 allele (18). Recently, studies using several mutant mice lacking HB-EGF expression have revealed that HB-EGF, in conjunction with ErbB receptors, has a critical role in normal cardiac valve formation at both cushion formation and tissue remodeling stages (37).…”

“…Interestingly, although common clinical features were found in NS patients with different genetic mutations, substantial phenotypic variations were observed. For instance, pulmonic stenosis is more commonly observed among individuals with mutations in the PTPN11 allele, whereas hypertrophic cardiomyopathy is more closely associated with RAF1 mutations (18,19). These clinical observations suggested that multiple genetic factors contribute to the various phenotypes of NS and/or JMML.…”

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…On a related note, some studies have found that, occasionally, mutations in BRAF and MEK1 can result in a phenotype more similar to NS or NSML than to typical CFC (Nystrom et al 2008;Nishi et al 2015;Sarkozy et al 2009). This finding has resulted in some debate regarding whether these individuals can be diagnosed as having a Noonan-like syndrome or whether they simply exhibit a milder phenotype of CFC (Neri et al 2008).…”

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway

“…Oxidation rates of [U-14 C]malate were measured in the presence of malonate (inhibitor of SDH) to prevent the oxidation of [2,[3][4][5][6][7][8][9][10][11][12][13][14] C]malate to proceed beyond one TCA cycle. ATP production was measured in incubations containing pyruvate, malate, creatine and ADP, in both the absence and presence (blank reaction) of arsenite.…”

“…All molecules regulate the Ras-MAPK cascade. 2 Mitochondrial dysfunction is the most common inborn error of metabolism in children, the diagnosis of which is based on characteristic clinical symptoms of multisystem involvement and on the presence of metabolic markers. Clinical diagnosis is possible using a validated scoring system (mitochondrial disease criteria, MDC score) considering clinical signs and symptoms, as well as biochemical abnormalities (eg, lactic acidemia, elevated serum alanine and urinary excretion of certain organic acids and Krebs' cycle intermediates).…”