A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe

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 respo nse to levodopa treatment and levodopa-induced dyskinesias, The gene respon sible for AR-JP was recently identified and designated parkin, We have anal ysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozyg ous deletion of exon 4 could be demonstrated. By direct sequencing of the e xons in the index patients of the remaining 34 families, eight previously u ndescribed point. mutations (homozygous or heterozygous) were detected in e ight families that included 20 patients, The mutations segregated with the disease in the families and were not detected on 110-166 control chromosome s. Four mutations caused truncation of the parkin protein. Three were frame shifts (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 import ant for the function of the parkin protein, since they result in the same p henotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations i n the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from tha t of idiopathic PD. This study has shown that a wide variety of different m utations in the parkin gene are a common cause of autosomal recessive parki nsonism in Europe and that different types of point mutations seem to be mo re frequently responsible for the disease phenotype than are deletions.