Cardiovascular disorders

MYLK-related thoracic aortic aneurysms and aortic dissections; Aortic aneurysm; Aortic aneurysm, familial thoracic 7; Thoracic aortic aneurysms and aortic dissections; Giardiasis; Intracranial vasospasm; Aortic aneurysm, Familial thoracic 4

Aortic aneurysm is a bulging or 'ballooning' in the wall of the aorta, posing a risk of bursting and causing internal bleeding and death. Aortic aneurysm may occur in either the thoracic aorta or the abdominal aorta. Giardiasis is a diarrheal condition caused by infection with Giardia, a microscopic parasite found on surfaces or in soil, food, or water that has been contaminated with feces from an affected individual. Intracranial vasospasm is a condition characterized by the spasm of the muscle in the walls of blood vessels leading to vasoconstriction of the vessel. This vasoconstriction can lead to tissue ischemia and death (necrosis). Mutations in the MLCK1 gene have been observed in patients with aortic aneuryms, including a S1759P substitution mutation and a R1480X termination mutation. The S1759P mutation was located in the alpha-helix of the calmodulin-binding domain of the protein and is predicted to result in the loss of MLCK1 catalytic activity due to altered binding affinity of calmodulin. In vitro enzymatic analysis of the S1759P mutant protein revealed a 6-fold decrease in catalytic activity compared to the wild-type protein. In animal studies, mice lacking MLCK1 displayed increased accumulation of proteoglycans in aortic tissues, combined with elevated expression of lumican, decorin and collagen in the adventitial layer and an overall increase in aortic type III collagen expression as compared to controls. In addition, the expression of elastin-degrading metalloproteinase MMP2 was elevated in the aortic tissue of mice lacking MLCK1, although the elastic fibres were not degraded in the corresponding aortic media. Therefore, loss-of-function of the MLCK1 is associated with extensive changes in the extracellular matrix and connective tissue profile of aortic tissue, potentially predisposing the patient to a higher risk of aortic aneurysm.
 

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= -78, p<0.015); Breast epithelial carcinomas (%CFC= -66, p<0.006); Breast epithelial cell carcinomas (%CFC= -45, p<0.017); Cervical cancer stage 2B (%CFC= -46, p<0.077); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +107, p<0.019); Colon mucosal cell adenomas (%CFC= -78, p<0.0001); Colorectal adenocarcinomas (early onset) (%CFC= +311, p<0.013); Lung adenocarcinomas (%CFC= -62, p<0.0001); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +203, p<0.0008); Pituitary adenomas (ACTH-secreting) (%CFC= +124); Prostate cancer - metastatic (%CFC= -81, p<0.0001); Skin fibrosarcomas (%CFC= -84); Skin melanomas - malignant (%CFC= -90, p<0.005); Skin squamous cell carcinomas (%CFC= -62, p<0.04); Uterine leiomyomas from fibroids (%CFC= +73, p<0.009); and Vulvar intraepithelial neoplasia (%CFC= -73, p<0.002). The COSMIC website notes an up-regulated expression score for MLCK1 in diverse human cancers of 303, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 2 for this protein kinase in human cancers was 97% lower than 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: 0.09 % in 24770 diverse cancer specimens. This rate is only 14 % higher 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: 0.51 % in 864 skin cancers tested; 0.28 % in 603 endometrium cancers tested; 0.27 % in 589 stomach cancers tested; 0.26 % in 1270 large intestine cancers tested; 0.14 % in 1822 lung cancers tested; 0.13 % in 548 urinary tract cancers tested; 0.11 % in 238 bone cancers tested; 0.08 % in 65 Meninges cancers tested; 0.08 % in 273 cervix cancers tested; 0.07 % in 881 prostate cancers tested; 0.07 % in 833 ovary cancers tested; 0.07 % in 1512 liver cancers tested; 0.07 % in 1316 breast cancers tested; 0.06 % in 942 upper aerodigestive tract cancers tested; 0.06 % in 710 oesophagus cancers tested; 0.06 % in 558 thyroid cancers tested; 0.04 % in 127 biliary tract cancers tested.

Most frequent mutations with the number of reports indicated in brackets: A1099T (9); A350T (4).

Only 5 deletions, 1 insertion and no complex mutations are noted on the COSMIC website.