BRAF is a proto-oncogene that encodes a serine-threonine kinase, a member of the Raf/Mil family of kinases. These enzymes function in the RAS/MAPK mitogenic signaling pathway. This pathway is associated with stimulating cell growth, division, differentiation, movement, and senescence. BRAF binds ATP and phosphorylates substrates including MEK, directly affecting mitogen signaling and growth enhancement. BRAF inhibits the growth suppressing activity of the retinoic acid-dependent transcription complex.
BRAF dysregulation results in increased enzymatic activity; in infants, this causes Cardiofaciocutaneous Syndrome, an intellectual disability disorder with heart, facial, skin, and hair abnormalities. Onset of BRAF dysregulation in later stages of life is associated with multiple cancers including malignant melanoma, thyroid carcinoma, colorectal cancer, non-Hodgkin lymphoma, lung adenocarcinoma, and non-small cell lung cancer.
BRAF is located on the q arm of chromosome 7 and is 208,814 bases long ranging from 140,715,951 to 140,924,764 base pairs pter. It contains 18 exons and translates into a 766aa long protein with a molecular weight of 84,437 Da. BRAF exhibits 3 conserved regions, an effector (RAS-GTP) binding domain, and a hinge domain which connects to the catalytic kinase domain. BRAF exists as a monomer, homodimer, and heterodimer (in combination with RAF1) with the latter structure being the most active form. The gene exhibits cytoplasmic expression in all tissues and is most expressed in the fetal brain, frontal cortex, cerebellum, pituitary gland, and testis. There are 13 paralog genes of BRAF as well as 1 pseudogene (BRAFP1) on the X chromosome.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism (IEM) and other genetic disorders. Among the cohort with non-IEM related genetic disorders in whom mutational pathogenicity was confirmed, 1 patient was diagnosed with cardiofaciocutaneous syndrome 1. A heterozygous missense transversion in BRAF (c.1914T>G; p.Asp638Glu) was identified as the cause.