Cardiovascular disorders

Wolff-Parkinson-White (WPW) syndrome

Wolff-Parkinson-White syndrome (WPW), also known as anomalous atrioventricular excitation, is a cardiovascular disease characterized by an abnormal heartbeat (arrhythmia) resulting from the uncoordinated conduction of electrical signals through the myocardium. This disease is one of the most common causes of rapid heart rate (tachycardia) in infants and children. Although the cause in most cases is unknown, autosomal dominant mutations in AMPKa1 have been implicated in the disorder. AMPKa1 is the catalytic subunit of AMP-activated protein kinase (AMPK), a protein kinase that functions as a cellular energy sensor and plays a key role in the regulation of cellular metabolism. When cellular ATP levels drop (e.g. during starvation situations), AMPK simultaneously promotes energy producing mechanisms and inhibits energy-consuming pathways, such as metabolite biosynthesis and cellular proliferation/growth. In general, several mutations in AMPK have been associated with abnormal cardiac function in humans, specifically ventricular hypertrophy and electrophysiological abnormalities, which are also characteristic of WPW syndrome. None of the observed mutations were correlated with changes in the phosphorylation state of the T172 residue of AMPK, but resulted in either a reduced AMP-dependence of protein activity or reduced AMP sensitivity. Transgenic mice overexpressing a mutant AMPK?2 subunit (N488I substitution mutation) displayed increased catalytic activity of AMPK, a 30-fold increase in accumulation of cardiac glycogen, left ventricular hypertrophy, and ventricular pre-excitation and dysfunction of the sino-atiral node. In addition, electrophysiological recordings revealed alternative pathways for electrical conduction through the atrial and ventricular musculature, consistent with the phenotype of WPW syndrome. Histological analysis of the tissue demonstrated that glycogen-filled cardiomyocytes disrupted the annulus fibrosis, which is an insulating layer that prevents the inappropriate electrical stimulation of the ventricles by atrial electrical activity. The loss of tissue integrity in the annulus fibrosis is thought to be the anatomical substrate mediating the pre-excitation of the ventricles, thus potentially explaining the symptoms of WPW syndrome. Therefore, aberrant activity of AMPK may play a important role in the development of WPW syndrome.
 

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: Brain glioblastomas (%CFC= -61, p<0.052); Brain oligodendrogliomas (%CFC= -74, p<0.023); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +525, p<0.0001); Oral squamous cell carcinomas (OSCC) (%CFC= +45, p<0.033); and Prostate cancer - primary (%CFC= +50, p<0.0002). The COSMIC website notes an up-regulated expression score for AMPKa1 in diverse human cancers of 712, which is 1.5-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 95 for this protein kinase in human cancers was 1.6-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.04 % in 25389 diverse cancer specimens. This rate is -44 % 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: 0.19 % in 1119 large intestine cancers tested.

None > 3 in 20,655 cancer specimens

No deletions, insertions or complex mutations are noted on the COSMIC website.