Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.
 ...
PMID:Germline gain-of-function mutations in SOS1 cause Noonan syndrome. 1719 80

Noonan syndrome, characterized by short stature, facial anomalies, heart disease and cryptorchidism in males, is an autosomal dominant, genetically heterogeneous disease. Approximately 50 % of Noonan syndrome cases are caused by gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase (SHP2) and 5 % are caused by KRAS mutations. Recently, a new mutation in SOS1 gene has been identified in approximately 20 % of cases of Noonan syndrome without PTPN11 mutation. That difference in genotype has a relationship with phenotype that we must investigate. We report a case of Noonan syndrome due to an SOS1 mutation; we describe his phenotype and subsequent outcome.
 ...
PMID:[SOS1 mutation: a new cause of Noonan syndrome]. 1839 82

Noonan syndrome (NS) is an autosomal-dominant genetic disorder associated with highly variable features, including heart disease, short stature, minor facial anomalies and learning disabilities. Recent gene discoveries have laid the groundwork for exploring whether variability in the NS phenotype is related to differences at the genetic level. In this study, we examine the influence of both genotype and nongenotypic factors on cognitive functioning. Data are presented from 65 individuals with NS (ages 4-18) who were evaluated using standardized measures of intellectual functioning. The cohort included 33 individuals with PTPN11 mutations, 6 individuals with SOS1 mutations, 1 individual with a BRAF mutation and 25 participants with negative, incomplete or no genetic testing. Results indicate that genotype differences may account for some of the variation in cognitive ability in NS. Whereas cognitive impairments were common among individuals with PTPN11 mutations and those with unknown mutations, all of the individuals with SOS1 mutations exhibited verbal and nonverbal cognitive skills in the average range or higher. Participants with N308D and N308S mutations in PTPN11 also showed no (or mild) cognitive delays. Additional influences such as hearing loss, motor dexterity and parental education levels accounted for significant variability in cognitive outcomes. Severity of cardiac disease was not related to cognitive functioning. Our results suggest that some NS-causing mutations have a more marked impact on cognitive skills than others.
 ...
PMID:Genotype differences in cognitive functioning in Noonan syndrome. 1907 16

Noonan syndrome (NS), the most common single-gene cause of congenital heart disease, is an autosomal dominant disorder that also features proportionate short stature, facial abnormalities, and an increased risk of myeloproliferative disease. Germline-activating mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, cause about half of NS cases; other causative alleles include KRAS, SOS1, and RAF1 mutants. We showed previously that knock-in mice bearing the NS mutant Ptpn11(D61G) on a mixed 129S4/SvJae X C57BL6/J background exhibit all major NS features, including a variety of cardiac defects, with variable penetrance. However, the cellular and molecular mechanisms underlying NS cardiac defects and whether genetic background and/or the specific NS mutation contribute to the NS phenotype remained unclear. Here, using an inducible knock-in approach, we show that all cardiac defects in NS result from mutant Shp2 expression in the endocardium, not in the myocardium or neural crest. Furthermore, the penetrance of NS defects is affected by genetic background and the specific Ptpn11 allele. Finally, ex vivo assays and pharmacological approaches show that NS mutants cause cardiac valve defects by increasing Erk MAPK activation, probably downstream of ErbB family receptor tyrosine kinases, extending the interval during which cardiac endocardial cells undergo endocardial-mesenchymal transformation. Our data provide a mechanistic underpinning for the cardiac defects in this disorder.
 ...
PMID:Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. 1925 46

Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.
 ...
PMID:Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype? 2134 Jan 58

Recently, germline mutations of NRAS have been shown to be associated with Noonan syndrome (NS), a relatively common developmental disorder characterized by short stature, congenital heart disease, and distinctive facial features. We report on the mutational analysis of NRAS in a cohort of 125 French patients with NS and no known mutation for PTPN11, KRAS, SOS1, MEK1, MEK2, RAF1, BRAF, and SHOC2. The c.179G>A (p.G60E) mutation was identified in two patients with typical NS, confirming that NRAS germline mutations are a rare cause of this syndrome. We also screened our cohort of 95 patients with juvenile myelomonocytic leukemia (JMML). Among 17 patients with NRAS-mutated JMML, none had clinical features suggestive of NS. None of the 11 JMML patients for which germline DNA was available had a constitutional NRAS mutation.
 ...
PMID:Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia. 2288 81

Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.
 ...
PMID:Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate. 3080 84

Although relatively uncommon, pathologists may encounter minimal inflammatory foci in the absence of typical structural heart disease; however, the clinicopathological significance of minimal inflammatory foci, including correlation with sudden unexpected death, is unexplored. From 1072 serial autopsy subjects, cases with unexplained minimal inflammatory foci, the extent of which was under 1% of the whole examined ventricle, were extracted to exclude cases with borderline/focal myocarditis resulting from local, systemic infection, or autoimmune mechanisms. Immunohistochemistry and genetic analysis targeting viral genomes and heart disease-related genes using next generation sequencing were performed. We detected 10 cases with unexplained minimal inflammatory foci (five males, five females, aged 15-68 years). The cause and/or manner of death were sudden unexpected death (6 cases, 60%), sudden unexpected death with epilepsy (1 case, 10%), drowning in a hot bath (1 case, 10%), and suicide (2 cases, 20%). In none of these cases was pathogen-derived DNA or RNA detected. In 8 of the 10 cases (80%), 17 possible pathogenic genetic variants causative for arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy; DSP was the most frequently involved gene (three cases with two different variants), followed by LAMA4 and MYBPC3 (two cases, two variants for each gene), LDB3 (two cases, one variant), and the remaining 10 variants occurred in seven cases (DSC2, RYR2, SOS1, SCN5A, SGCD, LPL, PKP2, MYH11, GATA6, and DSG2). All mutations were missense mutations. DSP_Lys1581Glu and DSC2_p.Thr275Met were classified according to American College of Medical Genetics and Genomics consensus statement guidelines as pathogenic or likely pathogenic for arrhythmogenic cardiomyopathy in three patients (30%). The remaining 15 variants were classified as potentially pathogenic variants. Unexplained minimal inflammatory foci may be an early sign of inherited cardiomyopathy, and such cases might already have arrhythmogenic potential that can lead to sudden unexpected death. Detection of minimal inflammatory foci by careful pathological examination may indicate the value of conducting comprehensive genetic analysis, even if significant structural abnormalities are not evident.
 ...
PMID:Minimal inflammatory foci of unknown etiology may be a tentative sign of early stage inherited cardiomyopathy. 3102 45

Noonan syndrome is a common genetic disease characterized by peculiar face, short stature, congenital heart disease and thoracic deformity. The pathogenesis of Noonan syndrome is mainly related to abnormal Ras-MAPK signal pathway which involves more than 16 genes including (PTPN11, SOS1, RAF1)] and KRAS. At present, there is a lack of experience in the diagnosis and treatment of Noonan syndrome in China. This guideline has summarized the clinical manifestation, pathogenesis, diagnostic criteria and treatment for Noonan syndrome, with an aim to improve the diagnostic level and clinical management of patients with this syndrome.
 ...
PMID:[Clinical practice guidelines for Noonan syndrome]. 3212 52