The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Tidyman, William E.; Rauen, Katherine A.

doi:10.1016/j.gde.2009.04.001

Cited by 652 publications

(578 citation statements)

References 54 publications

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“…24 NF1 belongs to a class of developmental syndromes called RASopathies, which are caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase pathway. 25 …”

Section: Functions Of Neurofibrominmentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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Although a mutation in the NF1 gene is the only factor required to initiate the neurocutaneous-skeletal neurofibromatosis 1 (NF1) syndrome, the pathoetiology of the multiple manifestations of this disease in different organ systems seems increasingly complex. The wide spectrum of different clinical phenotypes and their development, severity, and prognosis seem to result from the cross talk between numerous cell types, cell signaling networks, and cell-extracellular matrix interactions. The bi-allelic inactivation of the NF1 gene through a "second hit" seems to be of crucial importance to the development of certain manifestations, such as neurofibromas, café-au-lait macules, and glomus tumors. In each case, the second hit involves only one cell type, which is subsequently clonally expanded in a discrete lesion. Neurofibromas, which are emphasized in this review, and cutaneous neurofibromas in particular, are known to contain a subpopulation of NF1-diploinsufficient Schwann cells and a variety of NF1-haploinsufficient cell types. A recent study identified a multipotent precursor cell population with an NF1 ؉/؊ genotype that resides in human cutaneous neurofibromas and that has been suggested to play a role in their pathogenesis. café-au-lait macules and multiple benign cutaneous neurofibromas, which, typically, are detectable in adulthood by simple visual inspection.NF1 can affect nearly every organ system, and the complications vary between individuals, even within a single family. The clinical diagnosis is based on the presence of two or more of the following findings: six or more café-au-lait macules with diameters Ͼ5 mm in prepubertal patients and Ͼ15 mm in postpubertal patients; two or more neurofibromas of any type or one plexiform neurofibroma; axillary or inguinal freckling; optic glioma; two or more Lisch nodules of the iris; a distinctive osseous lesion, such as sphenoid wing dysplasia or pseudarthrosis; or a first-degree relative diagnosed as having NF1 according to the preceding criteria. 3 It has been suggested that a pathogenic mutation in the NF1 gene be added to the list of diagnostic criteria. 4 The most common complications of NF1 are included in the previously listed diagnostic criteria. Additional features include short stature, scoliosis, headache, speech disorders, attention deficit disorder and attention-deficit/ hyperactivity disorder, and learning disabilities. Rare complications, affecting Ͻ5% of patients, include epilepsy, hydrocephalus, cardiovascular problems, and dystrophic scoliosis. 5 The lifetime risk of malignant tumors arising from peripheral nerves is estimated to be 10% to 13%. 6 The pathoetiology of the complications in NF1 is, however, largely unknown. Genetic BackgroundNF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin. 7,8 The NF1 gene is located on chromosome band 17q11.2, spanning approximately 280 kb of genomic DNA, and is composed of 57 constitutive exons and 4 alternatively spliced exons (9a, 10a2, 23a, and 48a). 9 Howeve...

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Section: Functions Of Neurofibrominmentioning

confidence: 99%

The Pathoetiology of Neurofibromatosis 1

Jouhilahti

Peltonen

Heape

et al. 2011

The American Journal of Pathology

158

150

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“…Miscoding mutations in the B-RAF locus have also been observed in the germ line of patients with cardio-facio-cutaneous (CFC) syndrome, a congenital disorder that shares overlapping defects with other RASopathies such as Noonan, Costello, LEOPARD, and Legius syndromes as well as neurofibromatosis type I (4)(5)(6)(7)(8). 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).…”

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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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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“…The most plausible explanation for this finding would be a mutation in one of the genes of the same pathway. This pathway is mutated in cancer 18 and in a group of genetic conditions collectively known as RASopathies, 19 where all the mutations lead to an inappropriate activation of the pathway itself. For this reason a candidate gene analysis was performed in the two LCLIgAs for some of the genes involved in the RASopathies with the goal of identifying a mutation leading to silencing of ERK1/2, but no mutations were found in RAF1 and BRAF genes.…”

Section: Exome Sequencing and Bioinformatics Analysismentioning

confidence: 99%

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

Milillo¹,

Carpia²,

Costanzi

et al. 2015

Eur J Hum Genet

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IgA nephropathy (IgAN) represents the most common primary glomerulonephritis worldwide with a prevalence of 25-50% among patients with primary glomerulopathies. In~5-10% of the patients the disease segregates with an autosomal dominant (AD) pattern. Association studies identified loci on chromosomes 1q32, 6p21, 8p23, 17p13, 22q12, whereas classical linkage studies on AD families identified loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22. We have studied a large Sicilian family where IgAN segregates with an AD transmission. To identify the causal gene, the exomes of two affected and one unaffected individual have been sequenced. From the bioinformatics analysis a p.(Arg119Trp) variant in the SPRY2 gene was identified as the probable disease-causing mutation. Moreover, functional characterization of this variant showed that it is responsible for the inhibition of the MAPK/ERK1/2 pathway. The same effect was observed in two sporadic IgAN patients carriers of wild-type SPRY2, suggesting that downregulation of the MAPK/ERK1/2 pathway represents a common mechanism leading to IgAN.

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The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Cited by 652 publications

References 54 publications

The Pathoetiology of Neurofibromatosis 1

The Pathoetiology of Neurofibromatosis 1

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

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

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