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      Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

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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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          Most cited references12

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          Ubiquitin, proteasomes, and the regulation of intracellular protein degradation.

          Rapid degradation of specific proteins by ubiquitin/proteaseome-dependent pathways is a component of many cellular regulatory mechanisms. Recent work has shown that protein ubiquitination and deubiquitination are both mediated by large families of enzymes and that proteolysis can be modulated by alterations of the proteasome itself. The complexity of the ubiquitin system is reflected in the broad range of processes it regulates; these include key steps in cell cycle progression, processing of foreign proteins for presentation by class I MHC molecules, and the control of cell proliferation.
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            The PHD finger: implications for chromatin-mediated transcriptional regulation.

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              The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis.

              Three of the four yeast ubiquitin genes encode hybrid proteins which are cleaved to yield ubiquitin and previously unidentified ribosomal proteins. The transient association between ubiquitin and these proteins promotes their incorporation into nascent ribosomes and is required for efficient ribosome biogenesis. These results suggest a novel 'chaperone' function for ubiquitin, in which its covalent association with other proteins promotes the formation of specific cellular structures.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Science and Business Media LLC
                0028-0836
                1476-4687
                April 1998
                April 1998
                : 392
                : 6676
                : 605-608
                Article
                10.1038/33416
                9560156
                6a7d3718-6927-4a37-bfbd-ef5afcfd77fc
                © 1998

                http://www.springer.com/tdm

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