Genetic fine-mapping of the Iowan SNCA gene triplication in a patient with Parkinson's disease
Summary
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 | Zafar F, Valappil RA, Kim S, Johansen KK, Chang ALS, Tetrud JW, Eis PS, Hatchwell E, Langston JW, Dickson DW, Schüle B |
|---|---|
| Journal | NPJ Parkinson's disease |
| Publication Date | 2018;4:18 |
| PubMed | 29928688 |
| PubMed Central | PMC6003950 |
| DOI | 10.1038/s41531-018-0054-4 |