Mutation and phenotypic spectrum in patients with cardio‐facio‐cutaneous and Costello syndrome

Schulz, AL; Albrecht, Beate; Arıcı, Cumhur; Burgt, Ineke van der; Buske, Annegret; Gillessen‐Kaesbach, Gabriele; Heller, Raoul; Horn, Denise; Hübner, CA; Korenke, G. C.; König, Rainer; Kreß, Wolfram; Krüger, Gabriele; Meinecke, Peter; Mücke, J.; Plecko, Barbara; Rossier, Eva; Schinzel, Albert; Schulze, Andreas; Seemanová, E; Seidel, Heide; Spranger, Stefanie; Tüysüz, Beyhan; Uhrig, Sabine; Wieczorek, Dagmar; Kutsche, Kerstin; Zenker, Martin

doi:10.1111/j.1399-0004.2007.00931.x

Cited by 100 publications

(108 citation statements)

References 31 publications

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“…Consistent with the available records, 2 -4,16 -18,20 -22 these data indicate that MEK1 and MEK2 gene mutations 4 Niihori et al, 2 Nava et al, 16 Narumi et al, 3 Yoon et al, 20 Armour et al, 22 Gripp et al, 21 Schulz et al, 17 As facial dysmorphisms are not reported among Armour and Allanson's cohort, we compared the MEK-mutated CFCS cohort with our unpublished clinical data of 17 CFC BRAF-mutated positive patients. MEK1 and MEK2 mutations in CFC syndrome ML Dentici et al underlie a significant fraction of CFCS, accounting for approximately 20% of cases.…”

Section: Discussionsupporting

confidence: 76%

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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Section: Discussionsupporting

confidence: 76%

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

et al. 2009

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“…The number of fatal cases was 5/138 patients with p.G12S, 4/6 with p.G12C, 3/17 with p.G12A, 3/4 with p.G12D, 2/2 with p.G12V, 1/1 with p.G12E and 1/1 with p.E63K. 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The mortality of patients with p.G12C or p.G12D was significantly higher than that of the patients with the more common p.G12S (P¼0.026 by Fisher's exact test). Previous studies have shown that the p.G12V substitution has the highest transformative potential (p.G12V4p.G12A, p.G12S, p.G12C, p.G12D4p.G13D) and is the most frequently found mutation in human tumors.…”

Section: Discussionmentioning

confidence: 99%

“…3 It has been suggested that the CS diagnosis should be applied only to patients with a mutation in HRAS because of the high risk of malignancies associated with HRAS mutations and the relative homogeneity of the CS phenotype. 4 A total of 14 HRAS missense mutations and one duplication mutation have been reported in 185 patients with CS 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] or congenital myopathy with excess of muscle spindles. 24 Most of these mutations have previously been reported as somatic and oncogenic mutations in various tumors.…”

Section: Introductionmentioning

confidence: 99%

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

et al. 2011

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Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

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“…We synthesized mRNA for WT MEK1; 14 reported RASopathy MEK1 variants (11)(12)(13)(14)(15)(16)(17)(18), of which 5 are also found in cancer (37); and two MEK1 variants that are found in cancer alone (37) (Fig. 1A and SI Appendix, Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…In particular, multiple new mutations were identified in MEK1, a MAPK kinase (10) and an important target for anticancer therapeutics (11)(12)(13)(14)(15)(16)(17)(18)(19). Because it is commonly believed that cancer mutations would be embryonic lethal when inherited through the germ line, it might be expected that mutations that cause developmental disorders, but allow survival of the carrier, are weaker than those that cause cancer (20).…”

mentioning

confidence: 99%

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Jindal

Goyal

Yamaya

et al. 2017

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

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Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.T he Ras/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway is involved in essentially all aspects of organismal development, from the first cell divisions in the early embryo to postnatal development and growth (1-3). Given its critical function, it is not surprising that deregulated Ras/ MAPK signaling, resulting from either genetic or environmental perturbations, can lead to developmental abnormalities. A large class of such abnormalities, known as RASopathies, is associated with activating germ-line mutations in many components of the Ras pathway (4). Estimated to affect 1/1,000 human births, these abnormalities are characterized by a broad spectrum of phenotypes, including cardiac defects, craniofacial dysmorphisms, and neurocognitive delays (4). Although the origins of these phenotypes are still poorly understood, studies of model organisms show that many of the observed structural and functional defects can indeed be mimicked by targeted introduction of mutations found in RASopathies (5). Hundreds of such mutations have already been identified, and many more are likely to be discovered by the sequencing of affected individuals (6).Importantly, these studies identify new mutations in the very same components that are mutated in cancer and have been extensively studied both in vitro and in vivo (7-9). In particular, multiple new mutations were identified in MEK1, a MAPK kinase (10) and an important target for anticancer therapeutics (11)(12)(13)(14)(15)(16)(17)(18)(19). Because it is commonly believed that cancer mutations would be embryonic lethal when inherited through t...

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Mutation and phenotypic spectrum in patients with cardio‐facio‐cutaneous and Costello syndrome

Cited by 100 publications

References 31 publications

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

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

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

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