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

Dentici, Maria Lisa; Sárközy, Anna; Pantaleoni, Francesca; Carta, Claudio; Lepri, Francesca; Ferese, Rosangela; Cordeddu, Viviana; Martinelli, Simone; Briuglia, Silvana; Digilio, María Cristina; Zampino, Giuseppe; Tartaglia, Marco; Dallapiccola, Bruno

doi:10.1038/ejhg.2008.256

Cited by 70 publications

(75 citation statements)

References 26 publications

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“…Based on the literature, we find that an individual with F53S has more aberrant phenotypes than an individual with Y130C in the same study (SI Appendix, Table S5) (16). Similarly, L42F was found to be generally less severe than averaged data on two Y130C patients from the same study (SI Appendix, Table S5) (12). Although the patient data are not sufficient to perform statistics, these observations are largely consistent with our results.…”

Section: Discussionsupporting

confidence: 88%

“…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%

“…Currently, most phenotypic analyses in RASopathies are based on comparison at the gene level (23)(24)(25)(26), but there is high phenotypic heterogeneity within patients having mutations in the same gene (12). Independent of genetic background, it is important to know whether some mutations can cause more severe phenotypes than others.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Notably, several such secondary mutations correspond closely to missense germline variants that are observed in CFC syndrome (28). This disorder is characterized by mental retardation as well as cardiac and facial abnormalities and results from aberrant MAP kinase signaling during development.…”

Section: Discussionmentioning

confidence: 89%

MEK1 mutations confer resistance to MEK and B-RAF inhibition

Emery

Vijayendran

Zipser

et al. 2009

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

568

508

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Genetic alterations that activate the mitogen-activated protein kinase (MAP kinase) pathway occur commonly in cancer. For example, the majority of melanomas harbor mutations in the BRAF oncogene, which are predicted to confer enhanced sensitivity to pharmacologic MAP kinase inhibition (e.g., RAF or MEK inhibitors). We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro, as well as tumors obtained from relapsed patients following treatment with AZD6244, an allosteric MEK inhibitor. Most mutations conferring resistance to MEK inhibition in vitro populated the allosteric drug binding pocket or ␣-helix C and showed robust (Ϸ100-fold) resistance to allosteric MEK inhibition. Other mutations affected MEK1 codons located within or abutting the Nterminal negative regulatory helix (helix A), which also undergo gain-of-function germline mutations in cardio-facio-cutaneous (CFC) syndrome. One such mutation, MEK1(P124L), was identified in a resistant metastatic focus that emerged in a melanoma patient treated with AZD6244. Both MEK1(P124L) and MEK1(Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor. However, exposing BRAF-mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones. These results affirm the importance of MEK dependency in BRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications.BRAF ͉ drug resistance ͉ MAP kinase ͉ melanoma A pproximately one-third of all cancers harbor genetic alterations that aberrantly upregulate mitogen-activated protein kinase (MAPK)-dependent signal transduction (1). In the MAPK pathway, RAS oncoproteins activate RAF, MEK, and ERK kinases to direct key cell proliferative and survival signals. When rendered constitutively active by genetic mutation, the MAP kinase pathway is believed to confer ''oncogene dependency'' (2), an excessive reliance on its dysregulated activity for tumor viability. Therefore, protein kinases within this signaling cascade offer promising targets for novel anticancer therapeutics.In melanoma, uncontrolled MAP kinase pathway activity is nearly ubiquitous and occurs most commonly through gain-offunction mutations involving codon 600 of the B-RAF kinase (3) (BRAF V600E ; 50-70% of cases). Considerable preclinical evidence has associated the BRAF V600E mutation with heightened sensitivity to pharmacologic inhibition of RAF or MEK kinases (4, 5). Although early clinical trials of RAF and MEK inhibitors failed to show a substantial benefit (6, 7), recent phase I studies of selective RAF inhibitors have shown promising results in patients with BRAF-mutant tumors (8, 9). Thus, optimizing therapeutic efficacy while avoiding or bypassing the emergence of resistance to MAP kinase pathway inhibition will likely gain increasing importance in melanoma and other MAP kinasedriven cancers.He...

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Clinical Comparison of Overlapping Deletions of 19p13.3

Risheg¹,

Pasion

Sacharow

et al. 2013

American J of Med Genetics Pt A

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We present three patients with overlapping interstitial deletions of 19p13.3 identified by high resolution SNP microarray analysis. All three had a similar phenotype characterized by intellectual disability or developmental delay, structural heart abnormalities, large head relative to height and weight or macrocephaly, and minor facial anomalies. Deletion sizes ranged from 792 Kb to 1.0 Mb and included a common region arr [hg19] 19p13.3 (3,814,392-4,136,989), containing eight genes: ZFR2, ATCAY, NMRK2, DAPK3, EEF2, PIAS4, ZBTB7A, MAP2K2, and two non-coding RNA's MIR637 and SNORDU37. The patient phenotypes were compared with three previous single patient reports with similar interstitial 19p13.3 deletions and six additional patients from the DECIPHER and ISCA databases to determine if a common haploinsufficient phenotype for the region can be established.

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

Cited by 70 publications

References 26 publications

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

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

MEK1 mutations confer resistance to MEK and B-RAF inhibition

Clinical Comparison of Overlapping Deletions of 19p13.3

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