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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Author

Listed:
  • Tohru Kitada

    (Juntendo University School of Medicine
    Keio University School of Medicine)

  • Shuichi Asakawa

    (Keio University School of Medicine)

  • Nobutaka Hattori

    (Juntendo University School of Medicine)

  • Hiroto Matsumine

    (Juntendo University School of Medicine)

  • Yasuhiro Yamamura

    (Hiroshima University School of Medicine)

  • Shinsei Minoshima

    (Keio University School of Medicine)

  • Masayuki Yokochi

    (Tokyo Metropolitan Ebara Hospital)

  • Yoshikuni Mizuno

    (Juntendo University School of Medicine)

  • Nobuyoshi Shimizu

    (Keio University School of Medicine)

Abstract

Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

Suggested Citation

  • Tohru Kitada & Shuichi Asakawa & Nobutaka Hattori & Hiroto Matsumine & Yasuhiro Yamamura & Shinsei Minoshima & Masayuki Yokochi & Yoshikuni Mizuno & Nobuyoshi Shimizu, 1998. "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism," Nature, Nature, vol. 392(6676), pages 605-608, April.
  • Handle: RePEc:nat:nature:v:392:y:1998:i:6676:d:10.1038_33416
    DOI: 10.1038/33416
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    Cited by:

    1. Myoung Keun Lee & John R Shaffer & Elizabeth J Leslie & Ekaterina Orlova & Jenna C Carlson & Eleanor Feingold & Mary L Marazita & Seth M Weinberg, 2017. "Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2," PLOS ONE, Public Library of Science, vol. 12(4), pages 1-13, April.
    2. Irene H. Flønes & Lilah Toker & Dagny Ann Sandnes & Martina Castelli & Sepideh Mostafavi & Njål Lura & Omnia Shadad & Erika Fernandez-Vizarra & Cèlia Painous & Alexandra Pérez-Soriano & Yaroslau Compt, 2024. "Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Chuong B Do & Joyce Y Tung & Elizabeth Dorfman & Amy K Kiefer & Emily M Drabant & Uta Francke & Joanna L Mountain & Samuel M Goldman & Caroline M Tanner & J William Langston & Anne Wojcicki & Nicholas, 2011. "Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease," PLOS Genetics, Public Library of Science, vol. 7(6), pages 1-14, June.
    4. Syed F. Ali & Zbigniew K. Binienda & Syed Z. Imam, 2011. "Molecular Aspects of Dopaminergic Neurodegeneration: Gene-Environment Interaction in Parkin Dysfunction," IJERPH, MDPI, vol. 8(12), pages 1-12, December.
    5. International Parkinson's Disease Genomics Consortium (IPDGC) & Wellcome Trust Case Control Consortium 2 (WTCCC2), 2011. "A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease," PLOS Genetics, Public Library of Science, vol. 7(6), pages 1-9, June.
    6. Huan Yang & Caroline Sibilla & Raymond Liu & Jina Yun & Bruce A. Hay & Craig Blackstone & David C. Chan & Robert J. Harvey & Ming Guo, 2022. "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. Lene Clausen & Vasileios Voutsinos & Matteo Cagiada & Kristoffer E. Johansson & Martin Grønbæk-Thygesen & Snehal Nariya & Rachel L. Powell & Magnus K. N. Have & Vibe H. Oestergaard & Amelie Stein & Do, 2024. "A mutational atlas for Parkin proteostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Jenny Zhe Liao & Hyung-lok Chung & Claire Shih & Kenneth Kin Lam Wong & Debdeep Dutta & Zelha Nil & Catherine Grace Burns & Oguz Kanca & Ye-Jin Park & Zhongyuan Zuo & Paul C. Marcogliese & Katherine S, 2024. "Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Yunpeng Huang & Zhihui Wan & Yinglu Tang & Junxuan Xu & Bretton Laboret & Sree Nallamothu & Chenyu Yang & Boxiang Liu & Rongze Olivia Lu & Bingwei Lu & Juan Feng & Jing Cao & Susan Hayflick & Zhihao W, 2022. "Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Federico Miozzo & Eva P. Valencia-Alarcón & Luca Stickley & Michaëla Majcin Dorcikova & Francesco Petrelli & Damla Tas & Nicolas Loncle & Irina Nikonenko & Peter Bou Dib & Emi Nagoshi, 2022. "Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    11. Michael W Nagle & Jeanne C Latourelle & Adam Labadorf & Alexandra Dumitriu & Tiffany C Hadzi & Thomas G Beach & Richard H Myers, 2016. "The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane," PLOS ONE, Public Library of Science, vol. 11(8), pages 1-14, August.

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