Germline mutation in BRAF codon 600 is compatible with human development: De novo p.V600G mutation identified in a patient with CFC syndrome

Greenwood Genetic Center, Greenwood, SC 29646, USA.
Clinical Genetics (Impact Factor: 3.93). 05/2011; 79(5):468-74. DOI: 10.1111/j.1399-0004.2010.01495.x
Source: PubMed


Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome.
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.

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    • "BRAF. The majority fall into the high-or intermediate-activity class (Rodriguez-Viciana et al. 2006), with only seven also being found in human cancer samples; namely, G469E, F468S, L485F, F595L, V600G, and K601E in CFC patients (Rodriguez-Viciana et al. 2006; Champion et al. 2011), with the intermediateactivity L597V mutation being detected in both NS and CFC patients (Sarkozy et al. 2009; Pierpont et al. 2010). How the same mutations can promote developmental abnormalities when constitutively expressed but cancer when acquired somatically is a critical question to address and is likely related to mechanisms of downstream MEK/ERK pathway activation under different contexts. "
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