Genomic multiplication of the alpha-synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non-allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN(®) imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype-phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication.
© 2011 Wiley-Liss, Inc.