title: 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(1/2)-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.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California 94115, USA. rauenk@peds.ucsf.edu
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.forename: William E
authors.initials: WE
authors.lastname: Tidyman
authors.forename: Anne L
authors.initials: AL
authors.lastname: Estep
authors.forename: Srirangan
authors.initials: S
authors.lastname: Sampath
authors.forename: Henry M
authors.initials: HM
authors.lastname: Peltier
authors.forename: Sherri J
authors.initials: SJ
authors.lastname: Bale
authors.forename: Yves
authors.initials: Y
authors.lastname: Lacassie
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology* / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D019066:Facies; D005191:Family Characteristics; D005260:Female; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D040582:Inheritance Patterns / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D013577:Syndrome
chemical_list: D050505:Mutant Proteins; C482128:MAP2K2 protein, human; D048370:MAP Kinase Kinase 2