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Cited by 5,227Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeurological diseases and metabolism

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Kitada, Tohru, Asakawa, Shuichi, Hattori, Nobutaka, Matsumine, Hiroto, Yamamura, Yasuhiro, Minoshima, Shinsei, Yokochi, Masayuki, Mizuno, Yoshikuni +1 more·1998·Nature
DOI 10.1038/33416
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Abstract

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Autosomal recessive juvenile parkinsonism (AR-JP) maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253; the former is deleted in one Japanese AR-JP patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA done 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'.

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  • Mutations in PARKIN and PINK1 are the leading causes of autosomal recessive Parkinson's disease.

    “Mutations in PARKIN and PINK1 are the leading causes of autosomal recessive PD [9, 10].”

    From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [9]

  • Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD.

    “Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD [22,23,24,94,95,96].”

    From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [22]

  • A causal association has been established between autosomal recessive forms of PD and mutations affecting the mitophagy regulators PINK1 and PRKN/PARK2.

    “A causal association has been established between autosomal recessive forms of PD and mutations affecting the mitophagy regulators PINK1 (PTEN‐induced putative kinase 1) and PRKN/PARK2 (Parkin RBR E3 ubiquitin protein ligase) (Kitada et al, 1998; Valente et al, 2004; Narendra et al, 2008; Matsuda et al, 2010).”

    From Autophagy in major human diseases (2021) · cites this paper as Kitada et al, 1998

  • The most studied mechanism for mitophagy in mammalian cells is mediated by the cytoplasmic E3 ubiquitin ligase PARKIN and the mitochondrial membrane kinase PINK1.

    “The most studied mechanism for mitophagy in mammalian cells is mediated by the cytoplasmic E3 ubiquitin ligase PARKIN [210] and the mitochondrial membrane kinase PINK1 [211].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [210]

  • Homozygous or compound heterozygous mutations of genes encoding PINK1 and Parkin lead to selective degeneration of midbrain dopaminergic neurons and cause autosomal recessive early-onset Parkinson's disease.

    “Homozygous or compound heterozygous mutations of genes encoding PINK1 and Parkin lead to the selective degeneration of midbrain dopaminergic neurons and cause autosomal recessive early-onset Parkinson's disease (PD) (Kitada et al., 1998, Valente et al., 2004).”

    From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Kitada et al., 1998

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Authors
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., & Shimizu, N.
Affiliations
  • Juntendo University (JP)
  • Keio University (JP)
  • Hiroshima University (JP)
  • Ebara Hospital (JP)
Corresponding author
Shimizu, Nobuyoshi
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
1998-04
Volume
392
Issue
6676
Pages
605-608
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/33416
OpenAlex
W1877873625
Cited by
5,227
References
29
Citations by year
2026: 113 · 2025: 122 · 2024: 189 · 2023: 182 · 2022: 183 · 2021: 244 · 2020: 231 · 2019: 186 · 2018: 183 · 2017: 219 · 2016: 206 · 2015: 207 · 2014: 192 · 2013: 232 · 2012: 212
FWCI
81.80
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
parkin gene, autosomal recessive juvenile parkinsonism, Parkinson's disease, positional cloning, ubiquitin-like proteins, exon deletion, substantia nigra, gene mapping
MeSH terms
Adult, Amino Acid Sequence, Chromosomes, Human, Pair 6, Exons, Female, Genes, Recessive, Humans, Introns, Ligases, Male, Molecular Sequence Data, Parkinson Disease, Pedigree, Proteins, Ubiquitins, Blotting, Southern, Blotting, Northern, Polymerase Chain Reaction, Gene Deletion, Sequence Homology, Amino Acid, Ubiquitin-Protein Ligases

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