Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease

Cornelis Blauwendraat¹, Demis A Kia², Lasse Pihlstrøm³, Ziv Gan-Or⁴, Suzanne Lesage⁵, J Raphael Gibbs⁶, Jinhui Ding⁶, Roy N Alcalay⁷, Sharon Hassin-Baer⁸, Alan M Pittman², Janet Brooks⁶, Connor Edsall⁶, Sun Ju Chung⁹, Stefano Goldwurm¹⁰, Mathias Toft¹¹, Claudia Schulte¹²; International Parkinson's Disease Genomics Consortium (IPDGC), COURAGE-PD Consortium; Dena Hernandez⁶, Andrew B Singleton⁶, Mike A Nalls¹³, Alexis Brice⁵, Sonja W Scholz¹⁴, Nicholas W Wood¹⁵

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
² Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK.
³ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁴ Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
⁵ Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France.
⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁸ Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, The Movement Disorders Institute, Tel-Hashomer, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁹ Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
¹⁰ Parkinson Institute of Milan, ASST "Gaetano Pini/CTO", Milano, Italy; Department of Neuroscience, "Rita Levi Montalcini", University of Turin, Italy.
¹¹ Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹² Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
¹³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Founder/Consultant with Data Tecnica International, Glen Echo, MD, USA.
¹⁴ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁵ Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK. Electronic address: n.wood@ucl.ac.uk.

PMID: 29398121
PMCID: PMC5823280
DOI: 10.1016/j.neurobiolaging.2017.12.012

Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease

Cornelis Blauwendraat et al. Neurobiol Aging. 2018 Apr.

. 2018 Apr:64:159.e5-159.e8.

doi: 10.1016/j.neurobiolaging.2017.12.012. Epub 2017 Dec 20.

Authors

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
² Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK.
³ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁴ Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
⁵ Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France.
⁶ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁸ Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, The Movement Disorders Institute, Tel-Hashomer, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁹ Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
¹⁰ Parkinson Institute of Milan, ASST "Gaetano Pini/CTO", Milano, Italy; Department of Neuroscience, "Rita Levi Montalcini", University of Turin, Italy.
¹¹ Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹² Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
¹³ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Founder/Consultant with Data Tecnica International, Glen Echo, MD, USA.
¹⁴ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁵ Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK. Electronic address: n.wood@ucl.ac.uk.

PMID: 29398121
PMCID: PMC5823280
DOI: 10.1016/j.neurobiolaging.2017.12.012

Abstract

SNCA missense mutations are a rare cause of autosomal dominant Parkinson's disease (PD). To date, 6 missense mutations in SNCA have been nominated as causal. Here, we assess the frequency of these 6 mutations in public population databases and PD case-control data sets to determine their true pathogenicity. We found that 1 of the 6 reported SNCA mutations, His50Gln, was consistently identified in large population databases, and no enrichment was evident in PD cases compared to controls. These results suggest that His50Gln is probably not a pathogenic variant. This information is important to provide counseling for His50Gln carriers and has implications for the interpretation of His50Gln α-synuclein functional investigations.

Keywords: H50Q; His50Gln; Parkinson's disease; SNCA.

Published by Elsevier Inc.

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Figures

**Figure 1. Overview of the *SNCA* gene on DNA, mRNA and protein level**
The *SNCA* gene has six exons of which several are non-coding (light-blue). NB the *SNCA* gene is located on the antisense strand of the human genome. On mRNA level five exons are left totaling 423 nucleotides (NM_000345) which result in a 141-amino acid protein. All six missense mutations are located in exon two and three in relatively close proximity. When comparing pathogenicity algorithm scores (CADD (Quang et al., 2015), GERP (Davydov et al., 2010)) between the six missense variants, His50Gln scores very poor compared to the other five missense mutations.

See this image and copyright information in PMC

References

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Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease

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Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease

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