HtrA1

HTRA1, also known as HtrA serine peptidase 1, is a human gene that encodes a secreted serine protease of the HtrA family. The protein typically has an N-terminal signal sequence, a serine protease domain, and a C-terminal PDZ domain, enabling proteolytic activity in the extracellular environment and interactions with substrate proteins. HtrA1 is involved in protein quality control and extracellular matrix remodeling, and it can modulate signaling pathways by processing specific substrates.

Functionally, HtrA1 participates in the turnover of misfolded or damaged proteins and influences the composition and integrity of the extracellular matrix. It is implicated in regulation of transforming growth factor-beta (TGF-β) signaling through processing of latent TGF-β binding proteins and related components, thereby impacting vascular and connective tissue biology. The enzyme is expressed in multiple tissues, with notable presence in the brain, vasculature, retina, and connective tissues.

Clinically, HTRA1 is associated with cerebrovascular and ocular diseases. Biallelic mutations in HTRA1 cause CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy), a rare early-onset small vessel disease. HTRA1 variants can also underlie autosomal dominant cerebral small vessel disease. In age-related macular degeneration (AMD), common regulatory variants near HTRA1, such as those in the promoter region, are associated with increased disease risk, presumably by elevating HTRA1 expression.

Genetically, HTRA1 is located on chromosome 10; genetic testing for HTRA1 mutations is used in suspected CARASIL/CSVD cases, while AMD risk analyses may consider nearby regulatory variants. Research continues to clarify HTRA1’s substrates, regulation, and role in vascular and ocular pathophysiology.