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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism


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’.

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Figure 1: Genetic studies of family 1.
Figure 2: Amino-acid sequence of Parkin protein.
Figure 3: Amino-acid sequence homology between Parkin and the ubiquitin family proteins.
Figure 4: Genetic studies of family 2.
Figure 5: Northern blot analysis of parkin gene expression.

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We thank the four AR-JP families for blood samples, K. Nagamine and J. Kudoh for discussions, H. Harigai for assistance in manuscript preparation, and T. Tamura and Y. Shimizu for technical advice. This study was supported by the Ministry of Education, Science, Sports and Culture, Japan, and by the National Parkinson Foundation.

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Correspondence to Nobuyoshi Shimizu.

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Kitada, T., Asakawa, S., Hattori, N. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

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