caa a22 4500 445860685 CHVBK 20180317145441.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00439-011-1041-6 doi (NATIONALLICENCE)springer-10.1007/s00439-011-1041-6 Novel variant Pro143Ala in HTRA2 contributes to Parkinson's disease by inducing hyperphosphorylation of HTRA2 protein in mitochondria [Elektronische Daten] [Chin-Hsien Lin, Meng-Ling Chen, Grace Chen, Chun-Hwei Tai, Ruey-Meei Wu] Mutations in the gene encoding the mitochondrial protein high temperature requirement A2 (HTRA2) are inconsistently associated with a risk of Parkinson's disease (PD). We assessed the presence of HTRA2 mutations among patients with PD and performed functional assay of identified mutations or variants. Among the total 1,373 subjects, the entire HTRA2 coding region was sequenced in 113 early-onset PD (EOPD), 20 familial PD patients and 150 control subjects. An additional 390 sporadic late-onset PD patients and 700 controls were subsequently screened to validate possible mutations found in the first set. We identified two novel heterozygous variants, c.427C>G (Pro143Ala) and c.906 +3 G>A, in 2 (1.5%) EOPD patients. The missense variant, Pro143Ala, was also observed in one late-onset PD patient but was absent in total 850 control subjects (relative risk 2.3, 95% CI 1.5-2.8, P=0.04). Expressing Pro143Ala variant of HTRA2 in primary dopaminergic neurons causes neurite degeneration. Following exposure to rotenone, the ultra-structural mitochondrial abnormality, the percentage of mitochondrial dysfunction and apoptosis in cells carrying the HTRA2 Pro143Ala variant was significantly higher than wild-type cells. Mechanistically, protein level of phosphorylated HTRA2 was increased in cells carrying the Pro143Ala variant, suggesting Pro143Ala variant promotes HTRA2 phosphorylation with resultant mitochondrial dysfunction. Our results support a biologically relevant role of HTRA2 in PD susceptibility in Taiwanese. Further large-scale association studies are warranted to confirm the role of HTRA2 Pro143Ala variant in the risk of PD. The Author(s), 2011 Lin Chin-Hsien Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut Chen Meng-Ling Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut Chen Grace Department of Applied Chemistry, Providence University, Shalu, Taiwan aut Tai Chun-Hwei Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut Wu Ruey-Meei Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut Human Genetics Springer-Verlag 130/6(2011-12-01), 817-827 0340-6717 130:6<817 2011 130 439 https://doi.org/10.1007/s00439-011-1041-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-1041-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lin Chin-Hsien Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chen Meng-Ling Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Chen Grace Department of Applied Chemistry, Providence University, Shalu, Taiwan aut NATIONALLICENCE 700 1- Tai Chun-Hwei Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut NATIONALLICENCE 700 1- Wu Ruey-Meei Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 130/6(2011-12-01), 817-827 0340-6717 130:6<817 2011 130 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer