HTRA1

At least four mutations in the HTRA1 gene have been found to cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CARASIL. This condition is characterized by a highly increased risk of stroke, deterioration of cognitive function (dementia), premature hair loss (alopecia), and attacks of low back pain. These signs and symptoms usually become apparent in early to mid-adulthood.

The HTRA1 gene mutations responsible for CARASIL reduce or eliminate the function of the HTRA1 enzyme. As a result, the enzyme is not available to inhibit signaling by TGF-β proteins. Researchers suspect that abnormally increased TGF-β signaling alters the structure of small blood vessels, particularly in the brain. These blood vessel abnormalities increase the risk of stroke and lead to the death of nerve cells (neurons) in many areas of the brain. Dysregulation of TGF-β signaling may also underlie the hair loss and back pain seen in people with CARASIL, although the relationship between abnormal TGF-β signaling and these features is less clear.

The HTRA1 gene is located on the long (q) arm of chromosome 10 in a region known as 10q26. This region has been strongly associated with the risk of developing age-related macular degeneration, a common cause of vision loss in older adults. Researchers have identified several variations (polymorphisms) in the HTRA1 gene that may explain the association between the 10q26 region and age-related macular degeneration. One of the variants, known as rs11200638, is found in an area of the gene called the promoter region, which starts the production of the HTRA1 enzyme.

It is unclear how a polymorphism in the HTRA1 gene might be related to age-related macular degeneration. In the 10q26 region, the HTRA1 gene is located next to a gene called ARMS2; changes in this gene have also been studied as a risk factor for the disease. Because the two genes are so close together, it is difficult to tell whether changes in one gene or the other, or possibly changes in both genes, account for the increased disease risk. Age-related macular degeneration is a complex condition that likely results from a combination of multiple genetic and environmental factors.

The HTRA1 gene is less active (downregulated) in some cancerous tumors than in normal cells. Studies have found this gene downregulation in several forms of cancer, including ovarian cancer, cancer that occurs in the lining of the uterus (endometrial cancer), a form of skin cancer called melanoma, and a form of liver cancer called hepatocellular carcinoma. Having reduced amounts of the HTRA1 enzyme may be related to tumor progression, the risk that cancer will spread (metastasize) to other parts of the body, and resistance to treatment with chemotherapy. However, the mechanism by which downregulation of the HTRA1 gene influences cancer development and growth is unknown.