Strauss et al. (2005) described the phenotype of 4 German PD patients with a mutation in the HTRA2 gene. Clinical symptoms included typical features of PD including bradykinesia, tremor, and muscular rigidity. All symptoms responded well to levodopa ... Strauss et al. (2005) described the phenotype of 4 German PD patients with a mutation in the HTRA2 gene. Clinical symptoms included typical features of PD including bradykinesia, tremor, and muscular rigidity. All symptoms responded well to levodopa therapy. Age at disease onset ranged from 49 to 77 years (mean 57.3 +/- standard error of mean 13.3 years). Heterozygous carriers of the S141 mutant allele also reflected typical features of PD including a positive and sustained response to levodopa therapy. The mean age at onset was 55.3 +/- 11.0 years, similar to that of the total study cohort of 518 German patients with idiopathic PD (55.3 +/- 12.0 years).
Using a candidate gene approach based on the phenotype of motor neuron degeneration-2 (mnd2) mice, Strauss et al. (2005) performed a mutation screening of the HTRA2 gene (606441) in 518 German patients with PD. In 4 of the ... Using a candidate gene approach based on the phenotype of motor neuron degeneration-2 (mnd2) mice, Strauss et al. (2005) performed a mutation screening of the HTRA2 gene (606441) in 518 German patients with PD. In 4 of the patients they found a novel heterozygous mutation (G399S; 606441.0001). They also found that a novel polymorphism (A141S; 606441.0002) was associated with PD (P = 0.05). Both mutations resulted in defective activation of the protease activity of HTRA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant HTRA2 and to a lesser extent the S141 risk allele polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant HTRA2 were more susceptible to stress-induced death than were wildtype. Strauss et al. (2005) concluded that their results provided a novel link between mitochondrial dysfunction and neurodegeneration in PD. Simon-Sanchez and Singleton (2008), however, failed to find an association between the G399S or A141S variants and PD among 644 PD patients and 828 controls; in addition, no associations were observed after stratifying by age. Simon-Sanchez and Singleton (2008) concluded that variability at HTRA2 does not contribute to risk of PD.