NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis-Noonan Syndrome

Luca, Alessandro De; Bottillo, Irene; Sárközy, Anna; Carta, Claudio; Neri, Cinzia; Bellacchio, Emanuele; Schirinzi, Annalisa; Conti, Emanuela; Zampino, Giuseppe; Battaglia, Agatino; Majore, Silvia; Rinaldi, Maria Michela; Carella, Massimo; Marino, Bruno; Pizzuti, Antonio; Digilio, María Cristina; Tartaglia, Marco; Dallapiccola, Bruno

doi:10.1086/498454

Cited by 141 publications

(132 citation statements)

References 58 publications

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“…Duplicative reports were merged. In the absence of a single review of NF1 patients with molecular confirmation including cardiac information, we studied a large survey of patients clinically diagnosed with NIH consensus criteria [Lin et al, 2000], and two series of NF-Noonan patients associated with an identified NF1 mutation [Baralle et al, 2003;De Luca et al, 2005].…”

Section: Literature Review Cohortmentioning

confidence: 99%

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Lin

Alexander

Colan

et al. 2011

American J of Med Genetics Pt A

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108

106

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Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes (“RASopathies”). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non‐progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow‐up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one‐fourth of those with arrhythmia, but is generally self‐limited in the remaining three‐fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated. © 2011 Wiley‐Liss, Inc.

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Section: Literature Review Cohortmentioning

confidence: 99%

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Lin

Alexander

Colan

et al. 2011

American J of Med Genetics Pt A

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108

106

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“…No clear genotype-phenotype correlation for the cardiac phenotype in NF1 and/or NFNS has been suggested, although a trend of association was found between heart defects, NFNS and in-frame/single amino-acid substitution. 18 Given the previous observations of an increased prevalence of nontruncating mutations in NFNS, 18 of an excess of PS in patients with NF1, 23 particularly in patients with the non-truncating 3 bp exon 17 deletion, 9 we hypothesized that non-truncating mutations in NF1 may be responsible for particular disease features, especially those which overlap with other Ras-MAPK disorders. Here, we report our analysis of mutation type in patients with PS and NF1, WS or NFNS.…”

Section: Introductionmentioning

confidence: 96%

“…Although originally reported as a distinct condition, subsequent clinical 17 and molecular analysis has shown that the majority of NFNS patients have only NF1 gene mutations, with a significantly higher prevalence of nontruncating mutations, particularly in-frame deletions, than in typical NF1. 18,19 Two cases have been reported with both NF1 and PTPN11 mutations. In one, the patient inherited the PTPN11 gene mutation from a parent and had a de novo NF1 mutation, 20 and in the other a de novo PTPN11 gene mutation with inherited NF1.…”

Section: Introductionmentioning

confidence: 99%

“…21 Although molecular diagnostics have added to our understanding of these conditions, there remains considerable overlap: the same mutations have been seen in NF1 with no features of NFNS. 18 Some of the cases with the c.2970_2972delAAT exon 17 mutation were clinically diagnosed as NFNS or WS. 9 Individuals of all these three phenotypes: NF1, WS and NFNS, fulfill the NIH criteria for NF1 and have mutations in the NF1 gene.…”

Section: Introductionmentioning

confidence: 99%

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Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

et al. 2012

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Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35 ¼ 26% vs 25/2322 ¼ 1.1%, P valueo0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (Po0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (Po0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

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“…One important domain is the GAP related domain which [24], while in NF1 patients loss of the normal copy of the NF1 gene is found [44]. Some NF1 patients also have features of Noonan syndrome and "neurofibromatosis-Noonan syndrome" has been described as a separate entity [9], but NF1 gene mutations represent the major molecular event underlying neurofibromatosisNoonan syndrome [9].…”

Section: Neurofibromatosis Type 1 (Omim 162200)mentioning

confidence: 99%

What’s new in the neuro-cardio-facial-cutaneous syndromes?

Denayer

Legius

2007

Eur J Pediatr

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The RAS-MAPKinase pathway is a signal transduction cascade which has been studied extensively during the last decades for its role in human oncogenesis. Activation of this cascade is controlled by cycling of the RAS protein between an inactive and an active state and by phosphorylation of downstream proteins. The signalling cascade regulates cell proliferation, differentiation and survival. Disturbed RAS signalling in malignancies is caused by acquired somatic mutations in RAS genes or other components of this pathway. Recently, germline mutations in genes coding for different components of the RAS signalling cascade have been recognized as the cause of several phenotypically overlapping disorders, recently referred to as the neuro-cardio-facial-cutaneous syndromes. Neurofibromatosis type 1, Noonan, LEOPARD, Costello and cardiofaciocutaneous syndromes all present with variable degrees of psychomotor delay, congenital heart defects, facial dysmorphism, short stature, skin abnormalities and a predisposition for malignancy. These findings point to important roles for this evolutionary conserved pathway in oncogenesis, development, cognition and growth. Conclusion: it has become obvious in recent years that the neuro-cardio-facial-cutaneous syndromes all share a common genetic and pathophysiologic basis. Dysregulation of the RAS-MAPKinase pathway is caused by germline mutations in genes involved in this pathway. Undoubtedly more genes causing related syndromes will be discovered in the near future since there are still a substantial number of genes in the pathway that are not yet associated with a known syndrome. Protein-tyrosine phosphatase, nonreceptor-type 11 Eur J Pediatr (2007) 166:1091-1098 DOI 10.1007 Human genes and proteins are written in capital letters; murine genes and proteins in small letters. Genes are written in italic, proteins are written straight.

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NF1 Gene Mutations Represent the Major Molecular Event Underlying Neurofibromatosis-Noonan Syndrome

Cited by 141 publications

References 58 publications

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

What’s new in the neuro-cardio-facial-cutaneous syndromes?

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