MAP2K2/MEK2

Syndromic associated CHDs overview

Bicuspid aortic valve (1, 9.1%)

ASD (3, 27.3%)

Pulmonary valvar stenosis - congenital (7, 63.6%)

[edit] Synopsis

Cardiofaciocutaneous (CFC) syndrome (OMIM:115150) is a distinctive autosomal dominant disorder characterized by heart defects, facial dysmorphic features, mental handicap and ectodermal abnormalities. Several players of the RAS-MAPK pathway are involved in the pathogenesis of this entity.

• Cardio-facio-cutaneous syndrome: mutations in SOS1, BRAF, KRAS, MAP2K1/MEK1 and MAP2K2/MEK2

External references for MAP2K2/MEK2

• ensembl: ENSG00000126934
• OMIM: 601263
• Search miRBase for MAP2K2/MEK2
• Expression patterns from 4DXPress: MAP2K2/MEK2
• MGI: MGI:1346867
• ZFIN: ZDB-GENE-041027-1
• Wikipedia: MAP2K2/MEK2
• Search Wikiproteins: MAP2K2/MEK2
• Search Genetic Association Database: MAP2K2/MEK2
• Search GeneTests: MAP2K2/MEK2
• CHeartED:

Known phenotypes for MAP2K2/MEK2

Non-syndromic

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Syndromic

ASD

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:17704260 (population study with screening of similar CHD patients and normal controls ) Syndromes: Cardiofaciocutaneous (CFC) syndrome (OMIM:115150) is an autosomal dominant disorder characterized by distinctive facial appearance (high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, posteriorly angulated ears with prominent helices), heart defects (pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy), and mental retardation. Ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosis-like condition Incidence: Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:17704260 Incidence: 3/15 patients Comments: Nava et al. performed mutation analysis of the genes KRAS, BRAF, MEK1, MEK2, PTPN11 and HRAS in 40 patients with CFC, 20 with Costello and 70 with NS. Four MEK1 and 4 MEK2 mutations were identified in 15 individuals (CFC=8, CS=4 and NS=3). Heart defects were present in 6 of them: pulmonary valvar stenosis in 3 patients, ASD in 3 patients and 3 individuals developed hypertrophic cardiomyopathy. No further details about the gene-phenotype associations were available. Add another study.

Bicuspid aortic valve

Support: unconfirmed: a single case report References: PMID:16439621 (population study with screening of similar CHD patients and normal controls ) Syndromes: Cardiofaciocutaneous (CFC) syndrome (OMIM:115150) is an autosomal dominant disorder characterized by distinctive facial appearance (high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, posteriorly angulated ears with prominent helices), heart defects (pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy), and mental retardation. Ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosis-like condition Incidence: rare Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:16439621 Incidence: 1/1 patients Comments: Rodriguez-Viciana et al. performed mutation analysis in 23 individuals having CFC syndrome without HRAS or PTPN11 mutations. Eleven BRAF mutations were detected in 18 out of 23 individuals. Additionally, they performed mutation analysis for the MEK1 and MEK2 gene in the 5 patients remaining and detected 2 missense mutations in MEK1 and 1 mutation in MEK2. The patient with the MEK2 mutation presented with bicuspid aortic valve and developed a hypertrophic cardiomyopathy. Add another study.

Pulmonary valvar stenosis - congenital

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:16439621 (population study with screening of similar CHD patients and normal controls ) PMID:17704260 (population study with screening of similar CHD patients and normal controls ) PMID:20358587 (population study with screening of similar CHD patients and normal controls ) Syndromes: Cardiofaciocutaneous (CFC) syndrome (OMIM:115150) is an autosomal dominant disorder characterized by distinctive facial appearance (high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, posteriorly angulated ears with prominent helices), heart defects (pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy), and mental retardation. Ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosis-like condition Incidence: Comments: Studies: (3) [ show ] [ hide ] Reference: PMID:19156172 Incidence: 1/2 patients Comments: Dentici et al. performed mutation analysis for the MEK1 and MEK2 gene in 33 patients with CFC and 75 patients with Noonan syndrome (without mutations in PTPN11, SOS1 or RAF1). Two MEK2 mutations were detected in 2 out of 33 CFC patietns. One patients with a MEK2 mutation presented with pulmonary valvar and supravalvular stenosis associated with mild hypertorphic cardiomyopathy. No MEK2 mutations in the Noonan cohort. Reference: PMID:17704260 Incidence: 3/15 patients Comments: Nava et al. performed mutation analysis of the genes KRAS, BRAF, MEK1, MEK2, PTPN11 and HRAS in 40 patients with CFC, 20 with Costello and 70 with NS. Four MEK1 and 4 MEK2 mutations were identified in 15 individuals (CFC=8, CS=4 and NS=3). Heart defects were present in 6 of them: pulmonary valvar stenosis in 3 patients, ASD in 3 patients and 3 individuals developed hypertrophic cardiomyopathy. No further details about the gene-phenotype associations were available. Reference: PMID:20358587 Incidence: 3/9 patients Comments: Rauen KA et al., 2010 detected a mutation in the MEK2 gene in nine members of a four-generation family with features of cardio-facio-cutaneous syndrome. Mid pulmonary valvar stenosis was present in 3 out of 9 affected members. Add another study.

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Protein interaction partners

Patients reports for MAP2K2/MEK2

• case 12 Clinical data Phenotype

Translocations

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Mutations in MAP2K2/MEK2

Mutation (DNA)	Mutation (peptide)	CHD	Reference	Other features	Inheritence	Additional info.
c.383C>A	p.128P>Q	Pulmonary valvar stenosis - congenital	PMID:20358587	Cardiofaciocutaneous (CFC) syndrome (OMIM:115150)	Dominant Familial	show hide Genetic evidence Segregating ; mutation segregates with the CFC phenotype in the family in silico prediction Sorting Intolerant From Tolerant (SIFT) analysis predicted this MEK2 variant to be deleterious. Functional studies HEK 293T cells were transiently transfected with appropriate controls plasmids and MEK2 mutant plasmid. The p.P128Q MEK2 mutant had increased ERK phosphorylation compared to the level induced by empty vector, wild-type MEK2 and the negative kinase inactive control. This result indicates that the p.P128Q MEK2 mutant protein is a weak hypermorph (Rauen KA et al., 2010).. Comments

Representation of protein MAP2K2

Heart expression domain of MAP2K2/MEK2

No specified expression domain for MAP2K2/MEK2

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Associated CHDs found by automated text mining

AGeneApart Method

• Pulmonary stenosis (09.05.92) (sig = 0.626)

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Huge Navigator (Genopedia)

See complete results on Genopedia (including non CHD)

Heart defects

• abnorm multiple

• 4-31 congenital anomalies of the heart

• familial turner syndrome

• 4-40 congenital anomalies of the skin

This page contributors

• Jeroen Breckpot - CME Leuven (Belgium) (association, mutation, study)