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Published on: August 15, 2019
Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through
Katherine A Rauen1, William E Tidyman, Anne L Estep
1Department of Pediatrics, University of California San Francisco, San Francisco, California 94115, USA. rauenk@peds.ucsf.edu
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.
Insights
Cardio-facio-cutaneous (CFC) syndrome is a rare disorder caused by Ras/MAPK pathway mutations. This study identifies a novel, vertically transmitted MEK2 mutation contributing to CFC, expanding knowledge of germline mutations.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by dysmorphic features, cardiac defects, ectodermal anomalies, and developmental delay.
- It results from alterations in the Ras/mitogen-activated protein kinase (MAPK) pathway due to mutations in BRAF, MEK1, or MEK2.
Observation:
- A 7-month-old boy with clinical CFC diagnosis was found to have a novel c.383C-->A transversion in MEK2 exon 3 (p.P128Q).
- Phenotypic features of CFC were observed in family members, including the mother and half-sibling, who were also screened for the MEK2 mutation.
Findings:
- The novel MEK2 p.P128Q mutation was predicted as deleterious by SIFT analysis.
- Transient transfection and Western analysis demonstrated increased kinase activity of the mutant MEK2 protein, evidenced by elevated ERK phosphorylation.
Implications:
- This case represents the first reported instance of a vertically transmitted functional MEK mutation causing CFC syndrome.
- The findings enhance the understanding of germline mutations within the Ras/MAPK pathway and their role in CFC syndrome pathogenesis.
