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Molecular and functional analysis of a novel MEK2 mutation in cardio‐facio‐cutaneous syndrome: Transmission through four generations
Author(s) -
Rauen Katherine A.,
Tidyman William E.,
Estep Anne L.,
Sampath Srirangan,
Peltier Henry M.,
Bale Sherri J.,
Lacassie Yves
Publication year - 2010
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.33342
Subject(s) - mapk/erk pathway , mutation , missense mutation , proband , biology , exon , trametinib , hek 293 cells , germline mutation , kinase , phenotype , genetics , cancer research , gene
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 $7{\raise0.5ex\hbox{$\scriptstyle 1$}\kern-0.1em/\kern-0.15em\lower0.25ex\hbox{$\scriptstyle 2$}}$ ‐month‐old boy with a clinical diagnosis of CFC. Bidirectional sequence analysis of MEK2 revealed a novel c.383C → A transversion 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. Sorting Intolerant From Tolerant (SIFT) analysis determined the novel MEK2 p.P128Q to be deleterious. To corroborate the functional alteration of the novel mutant protein, transient transfection of HEK 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. © 2010 Wiley‐Liss, Inc.