The cardiofaciocutaneous syndrome

Roberts, Amy; Allanson, Judith; Jadico, Suzanne K.; Kavamura, Maria Inês; Noonan, Jacqueline A.; Opitz, John M.; Young, Terri L.; Neri, Giovanni

doi:10.1136/jmg.2006.042796

Cited by 219 publications

(248 citation statements)

References 65 publications

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“…Here, we have generated a mouse strain that expresses low levels of a constitutively active B-Raf V600E kinase, hoping to mimic the limited but constitutive levels of B-RAF kinase activity present in patients with CFC syndrome. Indeed, B-Raf +/LSLV600E mice display similar, albeit not identical, defects to those found in CFC patients, including reduced life span, small size, facial dysmorphism, and epileptic seizures (9). These mice also show upregulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients (11).…”

Section: B-raf +/Lslv600e Mice Display Craniofacial Dysmorphism and Dmentioning

confidence: 83%

“…All of these syndromes result from constitutive hyperactivation of the RAS/RAF/MEK/ERK signaling cascade, but they display unique characteristic features (8). CFC is characterized by craniofacial defects, short stature, cardiomegaly, ectodermal abnormalities, mental retardation, and neurological defects (9). About 75% of the patients molecularly diagnosed with CFC carry germ-line mutations in B-RAF (4,5,10).…”

mentioning

confidence: 99%

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Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Urosevic

Sauzeau

Soto-Montenegro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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RASopathies are a class of developmental syndromes that result from congenital mutations in key elements of the RAS/RAF/MEK signaling pathway. A well-recognized RASopathy is the cardiofacio-cutaneous (CFC) syndrome characterized by a distinctive facial appearance, heart defects, and mental retardation. Clinically diagnosed CFC patients carry germ-line mutations in four different genes, B-RAF, MEK1, MEK2, and K-RAS. B-RAF is by far the most commonly mutated locus, displaying mutations that most often result in constitutive activation of the B-RAF kinase. Here, we describe a mouse model for CFC generated by germ-line expression of a B-Raf LSLV600E allele. This targeted allele allows low levels of expression of B-Raf V600E , a constitutively active B-Raf kinase first identified in human melanoma. B-Raf +/LSLV600E mice are viable and display several of the characteristic features observed in CFC patients, including reduced life span, small size, facial dysmorphism, cardiomegaly, and epileptic seizures. These mice also show up-regulation of specific catecholamines and cataracts, two features detected in a low percentage of CFC patients. In addition, B-Raf +/LSLV600E mice develop neuroendocrine tumors, a pathology not observed in CFC patients. These mice may provide a means of better understanding the pathophysiology of at least some of the clinical features present in CFC patients. Moreover, they may serve as a tool to evaluate the potential therapeutic efficacy of B-RAF inhibitors and establish the precise window at which they could be effective against this congenital syndrome.

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Section: B-raf +/Lslv600e Mice Display Craniofacial Dysmorphism and Dmentioning

confidence: 83%

mentioning

confidence: 99%

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Urosevic

Sauzeau

Soto-Montenegro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…1 Pregnancies were complicated by polyhydramnios in four cases. Weight at birth was over the 97th percentile in two of them.…”

Section: Mutation Analysismentioning

confidence: 99%

“…1 CFCS is genetically heterogeneous, with mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes occurring in approximately 62.5 -90% of affected individuals. 2 -5 CFCS disease genes encode for signal transducers participating in the RAS -MAPK pathway, which is known to play a crucial role in development and oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations

et al. 2009

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Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotypephenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.

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“…As a result of a combined effort of various specialists led by Prof. Neri, a comprehensive review on CFC was published in 2006, including the follow up on 6 of the original cases published in 1986 as first report on the natural history of CFC syndrome [Roberts et al, 2006]. The report represented the joint experiences of the various specialists from the CFC Medical Advisory Board, who had seen hundreds of CFC patients both in their clinical practices and in the CFC family meetings.…”

mentioning

confidence: 99%

My memories of Professor Giovanni Neri: The cardiofaciocutaneous syndrome (CFC)

Kavamura

2013

American J of Med Genetics Pt A

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The cardiofaciocutaneous syndrome

Cited by 219 publications

References 65 publications

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Constitutive activation of B-Raf in the mouse germ line provides a model for human cardio-facio-cutaneous syndrome

Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype–phenotype correlations

My memories of Professor Giovanni Neri: The cardiofaciocutaneous syndrome (CFC)

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