Cancer, cardiovascular, neurological, endocrine, and respiratory disorders

Myocardial infarction; Pneumonia; Status Asthmaticus; Neuroleptic Malignant syndrome; Acute myocardial Infarction; Pericardial Effusion; Dysphagia; Atrioventricular block; Trichinosis; Protein S deficiency; Gas gangrene; Acute kidney failure (AKI, ARF); Legionnaires' disease; Acute mountain sickness (AMS); Compartment syndrome; Chronic progressive external ophthalmoplegia (PEO); Calciphylaxis; Nephropathia epidemica; Intermediate coronary syndrome; Erysipelas; Adult dermatomyositis; Bronchiolitis obliterans organizing pneumonia (BOOP); Scleromyxedema; Necrotizing fasciitis; Inferior myocardial Infarction; Vibrio vulnificus Infection; Silent myocardial infarction; Autoimmune hypoparathyroidism; Amyopathic dermatomyositis (ADM); Wandering spleen; Creatine phosphokinase, Elevated serum; Sine scleroderma

Serotonin Syndrome can arise from overdose of some drugs and the recreational use of others. Serotonin Syndrome can affect the bone marrow, bone, and brain tissues. >Acute Febrile Neutrophilic Dermatosis (SS) is characterized by the development of arthritis, fever, and painful skin lesions. SS has a relation to leukemia and vasculitis. Clathrin binding to PIK3C2A can be reduced through the L103A, L104A, L105A, D106A, and D107A mutations, in conjunction. S259A/D/E can inhibit phosphorylation of PIK3C2A but will have no effect on enzyme activity. Proteolysis has been inhibited with a PIK3C2A S259A mutation. The lipid kinase activity of PIK3C2A can be inhibited with a D1250A mutation, which will also mediate clathrin localization through the modulation of the clathrin-binding domain. The affinity for PIK3C2A to bind Phosphatidylinositol (4,5) bisphosphate can be decreased 5-fold with a L1491A mutation, decreased 7-fold with a R1488A or V1490A mutation, decreased 23-fold with a R1493A mutation, or fully inhibited with a R1503A mutation. >Status Asthmaticus is a respiratory disease that can be life threatening due to lack of response in patients to standard treatment. >The rare Neuroleptic Malignant Syndrome is a neuronal syndrome which can be characterized by sweating, high fever, fluctuating blood pressure, stupor, muscle rigidity, and autonomic dysfunction which can lead to life-threatening situations. >Pericardial Effusion is characterized by fluid build-up in the pericardial cavity. Trichinosis is a rare condition where parasitic helminthes can induce diarrhea, vomiting, and abdominal pain. >Protein S Deficiency is characterized by the increased risk of forming a thrombosis due to improper regulation of blood clotting factors. >Acute Kidney Failure (AKI, ARF) is characterized by the sudden onset of kidney failure and can affect the kidney, bone, or heart tissues. Legionnaires' Disease is a form of pneumonia arising from bacteria. >Acute Mountain Sickness (AMS) is a sensitivity to low partial oxygen pressure that occurs at high altitude. >Compartment Syndrome is a rare cardiovascular disease where pressure in a portion of the body is increased either transiently or chronically. >Chronic Progressive External Ophthalmoplegia (PEO) manifests as the loss of muscle function controlling eye or eyelid movement. PEO can affect the eye, skeletal muscles, and the retina. Calciphylaxis originates from the abnormal accumulation of calcium in the walls of vessels, leading to full or partial obstruction of blood flow. >Nephropathia Epidemica is a rare disorder that often begins with a fever, but can lead to kidney infection. Erysipelas is a skin rash localized to one region of the body and which often develops from a skin infection.> Adult Dermatomyositis has a relation to dermatocytosis and to calcinosis. >Bronchiolitis Obliterans Organizing Pneumonia is a rare condition where the bronchioles of the lung are constricted, partly inhibiting airflow. Scleromyxedema is characterized by an abnormal level of mucin in the skin. Necrotizing Fasciitis is characterized by bacterial infection on the skin's surface. >Vibrio Vulnificus Infection is a rare condition related to septic shock and liver disease. Autoimmune Hypoparathyroidismis has a relation to the proton pump inhibitor pathway and can affect the bone, liver, and or endothelial tissues. >Amyopathic Dermatomyositis (ADM) has a similar phenotype as dermatomyositis, except that muscle weakness does not occur in ADM. >Wandering Spleen is a rare disorder characterized by having no fixed location for the spleen due to the development of ligaments to hold the spleen in one place do not develop effectively. >Sine Scleroderma is a rare disorder characterized by the accumulation of fibrous scar tissue on various portions of the body. Sine Scleroderma only affects internal organs and does not often affect skin.
 

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 human Bladder carcinomas (%CFC= +122, p<0.0004). The COSMIC website notes an up-regulated expression score for PIK3C2A in diverse human cancers of 327, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 155 for this protein kinase in human cancers was 2.6-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. PIK3C2A can affect intracellular vesicle trafficking, insulin signalling, insulin secretion, glucose transporter translocation to the plasma membrane, and glucose uptake (controlled by insulin). Clathrin binding to PIK3C2A can be reduced through the L103A, L104A, L105A, D106A, and D107A mutations, in conjunction. S259A/D/E can inhibit phosphorylation of PIK3C2A but will have no effect on enzyme activity. Proteolysis can be inhibited with a PIK3C2A S259A mutation. The lipid kinase activity of PIK3C2A can be inhibited with a D1250A mutation, which will also mediate clathrin localization through the modulation of the clathrin-binding domain. The affinity for PIK3C2A to bind Ptdddins (4,5) bisphosphate can be decreased 5-fold with a L1491A mutation, decreased 7-fold with a R1488A or V1490A mutation, decreased 23-fold with a R1493A mutation, or fully inhibited with a R1503A mutation.

Percent mutation rates per 100 amino acids length in human cancers: 0.05 % in 25453 diverse cancer specimens. This rate is only -28 % lower than 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: 0.27 % in 1275 large intestine cancers tested; 0.19 % in 866 skin cancers tested; 0.19 % in 603 endometrium cancers tested; 0.18 % in 570 stomach cancers tested; 0.11 % in 548 urinary tract cancers tested; 0.09 % in 273 cervix cancers tested; 0.07 % in 1933 lung cancers tested; 0.07 % in 1512 liver cancers tested; 0.05 % in 127 biliary tract cancers tested; 0.04 % in 943 prostate cancers tested; 0.04 % in 710 oesophagus cancers tested; 0.04 % in 558 thyroid cancers tested; 0.04 % in 1345 kidney cancers tested; 0.03 % in 866 ovary cancers tested; 0.02 % in 382 soft tissue cancers tested; 0.02 % in 1468 pancreas cancers tested; 0.02 % in 1316 breast cancers tested; 0.02 % in 1078 upper aerodigestive tract cancers tested; 0.01 % in 2103 central nervous system cancers tested; 0.01 % in 1982 haematopoietic and lymphoid cancers tested.

Most frequent mutations with the number of reports indicated in brackets: M1183V (3); M1183I (2); F1206L (3); F1206S (2).

Only 4 deletions,5 insertions, and no complex mutations are noted on the COSMIC website.