Molecular and functional analysis of a novel MEK2 mutation in cardio‐facio‐cutaneous syndrome: Transmission through four generations

Abstract

Cardio-facio-cutaneous (CFC) syndrome is one of the RASopathies and is caused by alteration of activity through the Ras/mitogen-activated protein kinase (MAPK) pathway due to heterozygous de novo mutations in protein kinases BRAF, MEK1 or MEK2. CFC is a rare multiple congenital anomaly disorder in which individuals have characteristic dysmorphic features, cardiac defects, ectodermal anomalies and developmental delay. We report a 7 ½ month-old boy with a clinical diagnosis of CFC. Bidirectional sequence analysis of MEK2 revealed a novel c.383C→A transition in exon 3 resulting in a nonsynonymous missense substitution, p.P128Q. Other family members, including the proband’s mother and half-sibling, displayed phenotypic features of CFC and were also screened for the MEK2 mutation identified in the proband. SIFT (Sorting Intolerant From Tolerant) analysis determined the novel MEK2 p.P128Q to be deleterious. To corroborate the functional alteration of the novel mutant protein, transient transfection of 293T cells with subsequent Western analysis was used to demonstrate increased kinase activity, as measured by ERK phosphorylation. This first reported case of a vertically transmitted functional CFC MEK mutation further expands our understanding of germline mutations within the Ras/MAPK pathway.

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

“…It is very rare for individuals with CFC to reproduce. 14 Germline mosaicism has yet to be reported.…”

“…In ∼200 individuals with CFC reported in the literature, 3 have been found to have acute lymphoblastic leukemia, 10,14,72 one with non-Hodgkin lymphoma, 73 and one with large B-cell lymphoma. One individual with CFC (BRAF mutation) had a hepatoblastoma, possibly the result of postcardiac transplant immunosuppression.…”

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

“…CFC syndrome is a recognized autosomal dominant condition, but until recently all cases were reported as sporadic, with no familial inheritance. However, Rauen et al (2010) have now documented the first vertically transmitted MEK2 mutation through four generations of a family, segregating with those family members who have phenotypic features of CFC syndrome.…”

The RASopathies: Syndromes of Ras/MAPK Pathway Dysregulation

“…Although the mutations that cause CFC are in a well-known oncogenic pathway, it is as yet unclear if individuals with CFC syndrome are at an increased risk for malignancies. CFC certainly does not appear to have the malignancy risk of NS, CS, and NF1 (Rauen et al 2010;Kratz et al 2011). …”

“…CFC syndrome is transmitted in an autosomal dominant manner (Rauen et al 2010). However, in most cases, it is the result of a de novo dominant mutation since it is very rare for individuals with CFC to reproduce.…”