Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease

Veerle Bogaerts, Karen Nuytemans, Joke Reumers, Philippe Pals, Sebastiaan Engelborghs, Barbara Pickut, Ellen Corsmit, Karin Peeters, Joost Schymkowitz, Peter Paul De Deyn, Patrick Cras, Frederic Rousseau, Jessie Theuns, Christine Van Broeckhoven

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5′ and 3′ regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration.

Original languageEnglish (US)
Pages (from-to)832-840
Number of pages9
JournalHuman mutation
Issue number6
StatePublished - Jun 2008
Externally publishedYes


  • HTRA2
  • High temperature requirement protein A2
  • Mitochondrial serine protease
  • Parkinson disease
  • Regulatory variants

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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