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

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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article number18
Journalnpj Parkinson's Disease
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Neurology

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