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SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia

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Abstract

Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.

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Acknowledgments

We would like to thank all those who have contributed to our research, particularly the patients and families who donated DNA samples for this work. This work is supported by the Morris K. Udall Parkinson’s Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke P50NS072187), the Mayo Clinic Florida Research Committee, and the Mayo Clinic Center for Individualized Medicine.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Matt Baker, Monica Y. Sanchez-Contreras, Michael L. Hutton, Dennis W. Dickson, Owen A. Ross & Rosa Rademakers

  2. Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA

    Audrey J. Strongosky & Zbigniew K. Wszolek

  3. Complete Genomics, Mountain View, CA, USA

    Shan Yang & Will Ferguson

  4. Pacific Parkinson’s Research Center and National Parkinson Foundation Center of Excellence, Department of Neurology, University of British Columbia, Vancouver, BC, Canada

    Donald B. Calne, Susan Calne & A. Jon Stoessl

  5. Eastern Ontario Regional Genetics Program, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada

    Judith E. Allanson

  6. Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA

    Daniel F. Broderick

  7. Lilly Research Centre, Eli Lilly and Company, Windlesham, GU20 6PH, UK

    Michael L. Hutton

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  1. Matt Baker
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  2. Audrey J. Strongosky
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  14. Zbigniew K. Wszolek
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Corresponding author

Correspondence to Rosa Rademakers.

Additional information

Zbigniew K. Wszolek and Rosa Rademakers contributed equally to this study.

D. B. Calne and S. Calne are already retired in the affiliation they are being listed.

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Baker, M., Strongosky, A.J., Sanchez-Contreras, M.Y. et al. SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics 15, 23–30 (2014). https://doi.org/10.1007/s10048-013-0378-5

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