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

Abstract

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.

• Authors: Faria Zafar, Ruksana Azhu Valappil, Sam Kim, Krisztina K Johansen, Anne Lynn S Chang, James W Tetrud, Peggy S Eis, Eli Hatchwell, J William Langston, Dennis W Dickson, Birgitt Schüle
• Journal: NPJ Parkinson's disease (NPJ Parkinsons Dis) Vol. 4 Pg. 18 ( 2018) ISSN: 2373-8057 [Print] United States
• PMID: 29928688 (Publication Type: Journal Article)