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. 2009 Jun;17(6):733-40.
doi: 10.1038/ejhg.2008.256. Epub 2009 Jan 21.

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

Maria Lisa Dentici  1 , Anna Sarkozy, Francesca Pantaleoni, Claudio Carta, Francesca Lepri, Rosangela Ferese, Viviana Cordeddu, Simone Martinelli, Silvana Briuglia, Maria Cristina Digilio, Giuseppe Zampino, Marco Tartaglia, Bruno Dallapiccola
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Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations

Maria Lisa Dentici et al. Eur J Hum Genet. 2009 Jun.

Abstract

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 genotype-phenotype 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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Figures

Figure 1
Figure 1
MEK1 and MEK2 mutations in cardio-facio-cutaneous syndrome. Genomic characterization of the MEK1 and MEK2 genes. Exons are represented by bars and numbered. Orange boxes indicate regions coding for the protein kinase domain (residues 68–361 in MEK1 and 72–369 in MEK2). Earlier identified mutations are represented as blue squares,, , , , , , , whereas those identified in this study are colored yellow.
Figure 2
Figure 2
Dysmorphic features of subjects heterozygous for a MEK1 or MEK2 mutation. Pictures of cases N.2 (a and c) and N.6 (b and d). Note the thin and sparse hair (b), curly hair (a and c), absence of eyebrows (a, b and c), hyperkeratosis and wrinkled palm with wide squared tips (d).
See this image and copyright information in PMC

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