Cancer, genetic disorders

Noonan syndrome 5; Leopard syndrome; Leopard syndrome 2; Noonan syndrome; Cardiofaciocutaneous (CFC) syndrome; Encephalitis; Dengue disease; St. Louis encephalitis; Pulmonic stenosis; West Nile fever; Murray valley encephalitis; Kyasanur forest disease; Noonan syndrome 1; Leopard syndrome 1; Cardiomyopathy, dilated, 1w; Raf1-related noonan syndrome; Raf1-related leopard syndrome

Raf1 is linked to the rare Cardiofaciocutaneous Syndrome, which can affect the heart (cardio-), face (facio-), skin, and hair (cutaneous). Symptoms can include mild to severe cognitive disability, and developmental delay. Encephalitis is characterized by inflammation in the brain with symptoms ranging from flu-like to headache, fever, and vomiting. St. Louis Encephalitis is typically spread through a virus, is a rare neurological disorder, and is characterized by fever, headache, nausea, vomiting, and fatigue. Pulmonic stenosis links to congenital heart disease and is characterized by obstructed flow of blood from the right ventricle to the pulmonary artery. Kyasanur Forest Disease (KFD) is a rare infectious disease characterized by fever, headache, neck stiffness, muscle pain, cough, dehydration, and issue of bleeding. Cardiomyopathy, Dilated, 1w is a rare disorder characterized by stillbirth, and autosomal recessive x-linked dominant inheritance.
 

Pilocytic astrocytomas (PA); Lung adenomas

RAF1 appears to be an oncoprotein (OP). Cancer-related mutations in human tumours point to a gain of function of the protein kinase. The active form of the protein kinase normally acts to promote tumour cell proliferation. Overactive Raf-1 kinase phosphotransferase activity due to different mutations has been implicated in the pathogenesis of both Noonan and Leopard syndromes. >Noonan syndrome 5 (NS5) is a rare genetic disease that may manifest as cancer and is characterized by the abnormal development of multiple body parts resulting in distinctive facial construction, broad or webbed neck, short stature, bleeding issues, congenital heart anomalies, skeletal malformations, and developmental delay. In NS5, some common mutations observed include R256S, S259F, T260R, D486G, T491R, and S612T. The S257L or L613V mutations in NS5 have greater ERK1/2 (MAPK3/1) activation due to increased kinase phosphotransferase activity of Raf1. Its phosphotransferase activity can be increased, leading to enhanced ERK1/2 activation through a P261A, or P261L, or P261S, or a V263A mutation. In some cases of NS5, Raf1 kinase phosphotransferase activity can be decreased with a D486N or T491I mutation. >Leopard Syndrome is a rare yet very distinctive disorder where victims are marked with dark spots on their skin. They also suffer from abnormalities in the heart and genitalia, widely spaced eyes (ocular hypertelorism), pulmonary stenosis, short stature, and sensorineural deafness. S257L and L613V mutations are associated with Leopard syndrome 2, and these are also accompanied by increased downstream activation of ERK1/2. Many of the mutations in the Raf1 in both Noonan and Leopard syndromes are located in a motif flanking the S259 residue in the CR2 domain of the protein, which is critical for Raf-1 autoinhibition through 14-3-3 binding to phosphorylated S259. The S257L substitution mutation is also associated with other cancers. >Pilocytic Astrocytoma is a rare, benign, and slow growing tumour that develops in the brain or spinal cord. Inhibition of Raf1 phosphotransferase activity by the protein phosphatase PPP5C is impaired (no binding) with S338D and S339E mutations when these occur in conjunction with phosphomimetic Y340D and Y341D mutations in Raf1. This results in a constitutively active kinase, and extensive phosphorylation of S338. The T491D and T494D can increase kinase phosphotransferase activity but the kinase is still sensitive to PPP5C. Methylation of Raf1 can be inhibited with a R563K mutation, leading to increased stability and catalytic activity.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +132, p<0.0001); Brain glioblastomas (%CFC= -67, p<0.033); and Prostate cancer - primary (%CFC= +45, p<0.0001). The COSMIC website notes an up-regulated expression score for RAF1 in diverse human cancers of 560, which is 1.2-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 401 for this protein kinase in human cancers was 6.7-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.08 % in 25725 diverse cancer specimens. This rate is very similar (+ 10% higher) to the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.44 % in 1152 large intestine cancers tested; 0.33 % in 805 skin cancers tested; 0.31 % in 602 endometrium cancers tested; 0.31 % in 589 stomach cancers tested; 0.12 % in 1270 liver cancers tested; 0.1 % in 1941 lung cancers tested.

Most frequent mutations with the number of reports indicated in brackets: S257L (13); P261R (4).

Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.