Genetic fine-mapping of the Iowan SNCA gene triplication in a patient with Parkinson’s disease

• Published in: NPJ Parkinson's Disease Vol. 4; no. 1; pp. 18 - 7
• Main Authors: Zafar, Faria, Valappil, Ruksana Azhu, Kim, Sam, Johansen, Krisztina K., Chang, Anne Lynn S., Tetrud, James W., Eis, Peggy S., Hatchwell, Eli, Langston, J. William, Dickson, Dennis W., Schüle, Birgitt
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.06.2018; Nature Publishing Group
• Subjects: 631/208/1516; 692/617/375/1718; 692/699/375/365/1718; Biomedical and Life Sciences; Biomedicine; Brief Communication; Neurology; Neuropathology; Neurosciences; Parkinson's disease; United States > US; Iowa
• ISSN: 2373-8057; 2373-8057
• DOI: 10.1038/s41531-018-0054-4

The “Iowa kindred,” a large Iowan family with autosomal-dominant Parkinson’s disease, has been followed clinically since the 1920s at the Mayo Clinic. In 2003, the genetic cause was determined to be a 1.7 Mb triplication of the alpha-synuclein genomic locus. Affected individuals present with an early-onset, severe parkinsonism-dementia syndrome. Here, we present a descendant of the Iowa kindred with novel, disease-associated non-motor findings of reduced heart rate variability, complete anosmia, and a rare skin condition called colloid milium. At autopsy, key neuropathological findings were compatible with diffuse Lewy body disease. Using high-resolution comparative genomic hybridization (CGH) array analysis to fine-map the genomic breakpoints, we observed two independent recombination events of the SNCA locus that resulted in a genomic triplication of twelve genes, including SNCA , and the disruption of two genes, HERC6 and CCSER1 , at the genomic breakpoints. In conclusion, we provide further evidence that the mere two-fold overexpression of alpha-synuclein leads to a fulminant alpha-synucleinopathy with rapid progression and severe clinical and neuropathological features.