What are the early warning signs of CARASIL, the condition caused by HTRA1 mutations?

Early signs of CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) often appear in the second or third decade of life. Patients may experience chronic headaches, dizziness, and progressive weakness in the legs. As the disease progresses, symptoms can include difficulty walking, speech problems, and cognitive decline. Hair loss (alopecia) and spinal deformities (kyphosis) are also distinctive early physical signs that can help differentiate it from other stroke-like conditions.

How do HTRA1 mutations contribute to the development of age-related macular degeneration (AMD)?

HTRA1 mutations can alter the regulation of extracellular matrix proteins and TGF-beta signaling in the retina. This disruption may lead to abnormal accumulation of material under the retina and impaired maintenance of the retinal pigment epithelium. Over time, this contributes to the degeneration of the macula, the central part of the retina responsible for sharp vision, increasing the risk of developing AMD, particularly in individuals with specific genetic variants.

Is HTRA1 testing recommended for patients with a family history of early-onset strokes?

Genetic testing for HTRA1 mutations is recommended for individuals who present with early-onset strokes, particularly if they have a family history of similar symptoms, alopecia, or spinal issues. Since CARASIL is an autosomal recessive condition, testing can confirm the diagnosis and identify carrier status in family members. This information is crucial for genetic counseling and monitoring at-risk relatives for neurological and vascular changes.

What lifestyle modifications can help manage symptoms associated with HTRA1-related vascular conditions?

While there is no cure for genetic vascular conditions like CARASIL, managing cardiovascular risk factors is essential to slow progression. This includes maintaining strict blood pressure control, managing cholesterol levels, and avoiding smoking. Regular, moderate physical activity tailored to the patient's mobility level can help maintain circulation and muscle strength, but should always be supervised by a healthcare provider to prevent injury or overexertion.

HTRA1 gene

HTRA1 encodes a serine protease that regulates extracellular matrix remodeling and TGF‑β signaling, and mutations in this gene are associated with CARASIL, age‑related macular degeneration, and several cancers.

Overview

The HTRA1 gene provides instructions for making a protein that is found in many of the body's organs and tissues. This protein is a type of enzyme called a serine protease, which has an active center that cuts (cleaves) other proteins into smaller pieces. The HTRA1 enzyme helps break down many other kinds of proteins in the space surrounding cells (the extracellular matrix).

The HTRA1 enzyme also attaches (binds) to proteins in the transforming growth factor‑beta (TGF‑β) family and slows down (inhibits) their ability to send chemical signals. TGF‑β proteins normally help control many critical cell functions, including the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and the self‑destruction of cells (apoptosis). TGF‑β signaling also plays an important role in the formation of new blood vessels (angiogenesis).

Researchers have proposed several additional functions for the HTRA1 enzyme. It may play a role in the stabilization of microtubules, which are rigid, hollow fibers that make up the cell's structural framework (cytoskeleton). Additionally, the HTRA1 enzyme may be involved in depositing minerals, such as calcium and phosphorus, in developing bone (mineralization). Studies have also suggested that the HTRA1 enzyme acts as a tumor suppressor, a protein that helps prevent the development of cancerous tumors by keeping cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

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.

Age‑related macular degeneration

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.

Cancers

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.

Other Names for This Gene

ARMD7
HtrA
HTRA1_HUMAN
IGFBP5-protease
L56
ORF480
protease, serine, 11 (IGF binding)
PRSS11
serine protease HTRA1

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Tests of HTRA1

Scientific Articles on PubMed

PubMed

Catalog of Genes and Diseases from OMIM

HTRA SERINE PEPTIDASE 1; HTRA1

Gene and Variant Databases

NCBI Gene
ClinVar

References

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