2. Academic Validation
  3. Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy

  • Brain. 2020 Dec 5;143(11):3352-3373. doi: 10.1093/brain/awaa279.
Chin-Hsien Lin 1,  Pei-I Tsai 2,  Han-Yi Lin 1,  Nobutaka Hattori 3,  Manabu Funayama 4,  Beomseok Jeon 5,  Kota Sato 6,  Koji Abe 6,  Yohei Mukai 7,  Yuji Takahashi 7,  Yuanzhe Li 3,  Kenya Nishioka 3,  Hiroyo Yoshino 4,  Kensuke Daida 3,  Meng-Ling Chen 1,  Jay Cheng 1,  Cheng-Yen Huang 8,  Shiou-Ru Tzeng 9,  Yen-Sheng Wu 10,  Hsing-Jung Lai 1,  Hsin-Hsi Tsai 1,  Ruoh-Fang Yen 11,  Ni-Chung Lee 12,  Wen-Chun Lo 13,  Yu-Chien Hung 13,  Chih-Chiang Chan 13,  Yi-Ci Ke 1,  Chi-Chao Chao 1,  Sung-Tsang Hsieh 1 14 15,  Matthew Farrer 16 17,  Ruey-Meei Wu 1
Affiliations

Affiliations

  • 1 Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 2 Department of Biochemistry and Biophysics, University of California San Francisco, USA.
  • 3 Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  • 4 Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
  • 5 Department of Neurology, Movement Disorder Center, Seoul National University Hospital, Parkinson Study Group, Seoul National University College of Medicine, Seoul, Korea.
  • 6 Department of Neurology, Okayama University Medical School, Okayama, Japan.
  • 7 Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
  • 8 The first core laboratory, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 9 Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 10 Electron Microscope Laboratory of Tzong Jwo Jang, College of Medicine, Fu Jen Catholic University, Taipei, Taiwan.
  • 11 Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 12 Department of Medical Genetics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 13 Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 14 Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 15 Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 16 Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
  • 17 Center for Applied Neurogenetics, University of British Columbia, Canada.
PMID: 33141179 DOI: 10.1093/brain/awaa279
Abstract

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

Keywords

Parkinson’s disease; UQCRC1; mitochondria; respiratory chain complex III; ubiquinol-cytochrome c reductase core protein 1.

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