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) |
|---|---|
| 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 |
Fingerprint
Keywords
- BRAF
- Cardio-facio-cutaneous syndrome
- Germline
- P.V600E
- P.V600G
- Ras/MAPK pathway
- RASopathy
- Signal transduction
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Germline mutation in BRAF codon 600 is compatible with human development : De novo p.V600G mutation identified in a patient with CFC syndrome. / Champion, K. J.; Bunag, C.; Estep, A. L.; Jones, J. R.; Bolt, C. H.; Rogers, R. C.; Rauen, Katherine A; Everman, D.
In: Clinical Genetics, Vol. 79, No. 5, 05.2011, p. 468-474.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Germline mutation in BRAF codon 600 is compatible with human development
T2 - De novo p.V600G mutation identified in a patient with CFC syndrome
AU - Champion, K. J.
AU - Bunag, C.
AU - Estep, A. L.
AU - Jones, J. R.
AU - Bolt, C. H.
AU - Rogers, R. C.
AU - Rauen, Katherine A
AU - Everman, D.
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
KW - BRAF
KW - Cardio-facio-cutaneous syndrome
KW - Germline
KW - P.V600E
KW - P.V600G
KW - Ras/MAPK pathway
KW - RASopathy
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=79953738626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953738626&partnerID=8YFLogxK
U2 - 10.1111/j.1399-0004.2010.01495.x
DO - 10.1111/j.1399-0004.2010.01495.x
M3 - Article
C2 - 20735442
AN - SCOPUS:79953738626
VL - 79
SP - 468
EP - 474
JO - Clinical Genetics
JF - Clinical Genetics
SN - 0009-9163
IS - 5
ER -