Abstract
BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio-facio-cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild-type BRAF but is less strongly activating than the cancer-associated p.V600E mutation.
Original language | English (US) |
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Pages (from-to) | 468-474 |
Number of pages | 7 |
Journal | Clinical Genetics |
Volume | 79 |
Issue number | 5 |
DOIs | |
State | Published - May 2011 |
Externally published | Yes |
Keywords
- BRAF
- Cardio-facio-cutaneous syndrome
- Germline
- P.V600E
- P.V600G
- Ras/MAPK pathway
- RASopathy
- Signal transduction
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics