A Wide Variety of Mutations in the Parkin Gene Are Responsible for Autosomal Recessive Parkinsonism in Europe

作者：N. Abbas, C.B. Lücking, Sylvain Ricard, Alexandra Dürr, Vincenzo Bonifati, G. De Michele, Stephanie J. Bouley, Jenny R. Vaughan, Thomas Gasser, Roberto Marconi, E. Broussolle, Christine Brefel‐Courbon, Biswadjiet Sanjay Harhangi, Ben A. Oostra, E. Fabrizio, Georg Andrees Böhme, Laurent Pradier, Nicholas Wood, Alessandro Filla, Giuseppe Meco, Patrice Denèfle, Y. Agid, Alexis Brice, French Parkinson's Disease Genetics Study Group · 发表于：Human Molecular Genetics · 年份：1999 · DOI：10.1093/hmg/8.4.567 · 被引用次数：534 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Nuclear Receptors and Signaling、Neurological diseases and metabolism

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset p...