Genetic characterization of Omi/Htra2 (PARK13) in autosomal dominant and sporadic Parkinson’s disease

Objective/Rationale: 

Identification of DNA variations that cause familial/sporadic parkinsonism has provided insight into the biological pathways involved in disease. Thirteen loci (PARK1-13) have been proposed to influence susceptibility to parkinsonism and mutations in eight genes have been identified in patients. Segregation of some of these DNA changes with affected members of large parkinsonism families demonstrates they cause disease. However, when mutations appear in a small number of patients it is difficult to prove they are disease-related. 

Project Description: 

The role of Omi/Htra2 gene (PARK13) in familial and sporadic parkinsonism is unclear. One DNA change in Omi/Htra2 was observed in four sporadic Parkinson’s disease patients, resulting in a Serine amino acid replacing a Glycine at position 399 of the protein. This change was not found in healthy individuals. A second change (Alanine to Serine at position 141) was also reported as a ‘risk-factor’, as it was observed at a higher frequency in patients than compared to healthy subjects. We propose to DNA sequence Omi/Htra2 in affected members of families with Parkinson’s disease. In addition a patient-healthy control series will be used to examine the frequency of common variants in Omi/Htra2, such as the Alanine141Serine, that may associate with an increased risk of disease development. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease: 

Identification of genetic variants in Omi/Htra2 that affect disease susceptibility will generate new therapeutic targets and facilitate preclinical identification of ‘at risk’ carriers. The Htra2 protein is a serine protease which is targeted to the mitochondria and plays a role in apoptosis. The identified mutations are proposed to cause a ‘loss of function’, therefore protein replacement therapy or up-regulation of gene expression may benefit patients whose disease can be explained by variants in Omi/Htra2. 

Anticipated Outcome: 

This project will confirm if mutations in Omi/Htra2 are a common cause of familial Parkinson’s disease or if common variation increases the individual risk of disease development. If mutations that result in disease are confirmed this will lead to the generation of new cellular models to resolve the role of the Htra2 protein in disease.