Liver disorders

Hyperbiliverdinemia; Primary spontaneous pneumothorax; Spontaneous pneumothorax; Pneumothorax

Loss-of-function mutations in the protein have been associated with hyperbiliverdinemia, also known as green jaundice. Hyperbiliverdinemia is a rare liver disease characterized by a green discolouration of the skin, urine, serum, and other body fluids resulting from increased biliverdin accumulation in the body as a result of the inefficient conversion of the compound to bilirubin resulting from defective BLVRA function Interestingly, bilirubin is a potent antioxidant cytoprotectant and can effectively protect cells from excesses of hydrogen peroxide. Depletion of bilirubin in HeLa cells results in a substantial increase in reactive oxygen species (ROS) production and increased occurence of apoptosis. Mutations in the BLVRA gene have been reported in patients with hyperbiliverdinemia, including substitution mutations that result in premature translation termination (e.g. R18X and S44X) leading to the production of truncated BLVRA proteins. The R18X substitution mutation is predicted to truncate the BLVRA protein at a location N-terminal to the Tyr-97 residue, which is a critical activating phosphosite for BLVRA catalytic activity, thus representing a loss-of-function mutation. In addition, in vitro expression analysis of the S44X mutation in Xenopus laevis oocytes revealed that the mutation results in the production of a truncated BLVRA protein that completely lacks kinase catalytic activity. The occurence of the S44X mutation in hyperbiliverdinemia patients is correlated with a 3-fold higher biliverdin concentration as compared to control individuals. In addition to hyperbiliverdinemia, the BLVRA gene has also been associated with the occurence of pneumothorax, which is the abnormal accumulation of air or gas in the pleural cavity (i.e. the space that separates the lung from the chest wall). This condition usually results in a collapsed lung and difficulty breathing.
 

The COSMIC website notes an up-regulated expression score for BLVRA in diverse human cancers of 473, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 22 for this protein kinase in human cancers was 0.4-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: 0.07 % in 24523 diverse cancer specimens. This rate is only -3 % lower and is very similar 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: 0.31 % in 864 skin cancers tested; 0.29 % in 589 stomach cancers tested; 0.24 % in 1270 large intestine cancers tested; 0.1 % in 1316 breast cancers tested; 0.05 % in 1459 pancreas cancers tested.

None > 2 in 19,779 cancer specimens

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