Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation

Linden, Helen; Price, Susan

doi:10.1097/mcd.0b013e32833ff29d

Cited by 9 publications

(9 citation statements)

References 4 publications

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“…Increasing numbers of studies have shown that MEK1 and MEK2 have distinct functions in a wide variety of cells (41–44). Inhibition of ERK1/2 activation by U0126 or knockdown of MEK1 by small interfering RNA (siRNA) remarkably impaired HSV-2 production, whereas silencing of MEK2 had little effect (21).…”

Section: Discussionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway

Wang

Chen

Liao

et al. 2016

J Virol

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The mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK1/2/ERK1/2) cascade is involved in the replication of several members of the Flaviviridae family, including hepatitis C virus and dengue virus. The effects of the cascade on the replication of classical swine fever virus (CSFV), a fatal pestivirus of pigs, remain unknown. In this study, MEK2 was identified as a novel binding partner of the E2 protein of CSFV using yeast two-hybrid screening. The E2-MEK2 interaction was confirmed by glutathione S-transferase pulldown, coimmunoprecipitation, and laser confocal microscopy assays. The C termini of E2 (amino acids [aa] 890 to 1053) and MEK2 (aa 266 to 400) were mapped to be crucial for the interaction. Overexpression of MEK2 significantly promoted the replication of CSFV, whereas knockdown of MEK2 by lentivirus-mediated small hairpin RNAs dramatically inhibited CSFV replication. In addition, CSFV infection induced a biphasic activation of ERK1/2, the downstream signaling molecules of MEK2. Furthermore, the replication of CSFV was markedly inhibited in PK-15 cells treated with U0126, a specific inhibitor for MEK1/2/ERK1/2, whereas MEK2 did not affect CSFV replication after blocking the interferon-induced Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway by ruxolitinib, a JAK-STAT-specific inhibitor. Taken together, our results indicate that MEK2 positively regulates the replication of CSFV through inhibiting the JAK-STAT signaling pathway.IMPORTANCE Mitogen-activated protein kinase kinase 2 (MEK2) is a kinase that operates immediately upstream of extracellular regulated kinase 1/2 (ERK1/2) and links to Raf and ERK via phosphorylation. Currently, little is known about the role of MEK2 in the replication of classical swine fever virus (CSFV), a devastating porcine pestivirus. Here, we investigated the roles of MEK2 and the MEK2/ERK1/2 cascade in the growth of CSFV for the first time. We show that MEK2 positively regulates CSFV replication. Notably, we demonstrate that MEK2 promotes CSFV replication through inhibiting the interferon-induced JAK-STAT signaling pathway, a key antiviral pathway involved in innate immunity. Our work reveals a novel role of MEK2 in CSFV infection and sheds light on the molecular basis by which pestiviruses interact with the host cell.

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Section: Discussionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway

Wang

Chen

Liao

et al. 2016

J Virol

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“…MAP2K2 encoded a mitogen‐activated protein (MAP) kinase which belongs to the MAP kinase family. Specifically, MAP2K2 activates MAPK1/ERK2 and MAPK2/ERK2 by phosphorylation, thus regulating the mitogen growth factor signal transduction …”

Section: Discussionmentioning

confidence: 99%

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

et al. 2020

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The proximal 19p13.3 microdeletion/microduplication (prox19p13.3del/dup) syndrome is a recently described disorder with common clinical features including developmental delay, intellectual disability, speech delay, facial dysmorphic features with ear defects, anomalies of the hands and feet, umbilical hernia and hypotonia. While deletions are associated with macrocephaly, patients with duplications have microcephaly. The smallest region of overlap in multiple patients (113.5 kb) included three genes and one pseudogene, with a suggested major role of PIAS4 in determination of the phenotype and head size in these patients. Here, we refine the prox19p13.3del/dup with four additional patients: two with microdeletions, one with microduplication and one family with single‐nucleotide nonsense variant in PIAS4. The patient with the PIAS4 loss of function variant displayed a phenotype quite similar to deletion patients ‐including the macrocephaly and many other core features of the syndrome. Patient's SNV was inherited from her mother who is similarly affected. Thus, our data indicate that PIAS4 is a major contributor to the proximal 19p13.3del/dup syndrome phenotype. In summary, we report the first patient with a pathogenic variant in PIAS4‐ and three additional rearrangements at the proximal 19p13.3 locus. These observations add further evidence about the molecular basis of this microdeletion/microduplication syndrome.

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“…Rauen et al [] reported a family with transmission of the disease through four generations segregating with a previously unknown MEK2 mutation p.P128Q. Linden and Price [] observed another MEK2 mutation, p.G132D, in a mother and her two sons with CFC syndrome. Moreover, a novel KRAS mutation, p.Y71H, was recently found to be transmitted from a mother to her son, both clinically diagnosed with CFC syndrome [Stark et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…CFC syndrome is an established autosomal dominant condition, but the vast majority of affected individuals are sporadic occurrences due to presumed or proven de novo mutations. Only a few instances of familial transmission have been observed [Rauen et al, ; Linden and Price, ; Stark et al, ]. Four genes are known to cause CFC syndrome, namely BRAF , MEK1 , MEK2 , and KRAS .…”

Section: Introductionmentioning

confidence: 99%

Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation

Karaer

Lißewski

Zenker

2014

American J of Med Genetics Pt A

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Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It is typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure to thrive, and ectodermal abnormalities such as hyperkeratosis and sparse, brittle, curly hair. CFC syndrome is caused by dominant mutations in one of the four genes BRAF, MEK1, MEK2, and KRAS. Only three familial cases of CFC syndrome have been reported to date, whereas the vast majorities are sporadic cases due to de novo mutations. We report on a fourth familial case with transmission of CFC syndrome from father to son due to a novel heterozygous sequence change c.376A>G (p.N126D) in exon 3 of MEK2 gene. This observation further documents the possibility of vertical transmission of CFC syndrome, which appears to be associated with rare mutations and relatively mild intellectual disability in affected individual. The hypomorphic effect of specific mutations particularly regarding neurocognitive issues may be related to the variable fertility of affected individuals.

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Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation

Cited by 9 publications

References 4 publications

Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway

Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation

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