RGD Reference Report - Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease. - Rat Genome Database

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

Authors: Bogaerts, V  Nuytemans, K  Reumers, J  Pals, P  Engelborghs, S  Pickut, B  Corsmit, E  Peeters, K  Schymkowitz, J  De Deyn, PP  Cras, P  Rousseau, F  Theuns, J  Van Broeckhoven, C 
Citation: Bogaerts V, etal., Hum Mutat. 2008 Jun;29(6):832-40.
RGD ID: 5688393
Pubmed: PMID:18401856   (View Abstract at PubMed)
DOI: DOI:10.1002/humu.20713   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinson's disease  IAGP 5688393DNA:missense mutation:cds:p.R404W (human)RGD 
Parkinson's disease  ISOHTRA2 (Homo sapiens)5688393; 5688393DNA:missense mutation:cds:p.R404W (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Bradykinesia  IAGP 5688393DNA:missense mutation:cds:p.R404WRGD 
Lewy bodies  IAGP 5688393DNA:missense mutation:cds:p.R404WRGD 
Resting tremor  IAGP 5688393DNA:missense mutation:cds:p.R404WRGD 
Objects Annotated

Genes (Rattus norvegicus)
Htra2  (HtrA serine peptidase 2)

Genes (Mus musculus)
Htra2  (HtrA serine peptidase 2)

Genes (Homo sapiens)
HTRA2  (HtrA serine peptidase 2)


Additional Information