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A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease

Liu, Hui ; Koros, Christos ; Strohäker, Timo ; Schulte, Claudia ; Bozi, Maria ; Varvaresos, Stefanos ; Ibáñez de Opakua, Alain ; Simitsi, Athina Maria ; Bougea, Anastasia ; Voumvourakis, Konstantinos ; Maniati, Matina ; Papageorgiou, Sokratis G. ; Hauser, Ann‐Kathrin ; Becker, Stefan ; Zweckstetter, Markus ; Stefanis, Leonidas ; Gasser, Thomas

Movement disorders, 2021-07, Vol.36 (7), p.1624-1633 [Periódico revisado por pares]

Hoboken, USA: John Wiley & Sons, Inc

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  • Título:
    A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease
  • Autor: Liu, Hui ; Koros, Christos ; Strohäker, Timo ; Schulte, Claudia ; Bozi, Maria ; Varvaresos, Stefanos ; Ibáñez de Opakua, Alain ; Simitsi, Athina Maria ; Bougea, Anastasia ; Voumvourakis, Konstantinos ; Maniati, Matina ; Papageorgiou, Sokratis G. ; Hauser, Ann‐Kathrin ; Becker, Stefan ; Zweckstetter, Markus ; Stefanis, Leonidas ; Gasser, Thomas
  • Assuntos: A30G ; alpha-Synuclein - genetics ; Founder Effect ; Greece ; Haplotypes ; Humans ; Movement disorders ; Mutation ; Mutation - genetics ; Neurodegenerative diseases ; Parkinson Disease - genetics ; Parkinson's disease ; Parkinsonʼs disease ; SNCA ; Synuclein
  • É parte de: Movement disorders, 2021-07, Vol.36 (7), p.1624-1633
  • Notas: Nothing to report.
    Leonidas Stefanis and Markus Zweckstetter contributed equally to this article.
    This study was supported by the advanced grant “787679 ‐ LLPS‐NMR” of the European Research Council (to M.Z.), Hellenic Ministry of Education and Religion THALIS grant number 377206 (to L.S.), and by ongoing studies in familial PD cohorts supported by the Parkinsonʼs Disease Progression Markers Initiative (PPMI).
    Relevant conflicts of interest/financial disclosures
    Hui Liu and Christos Koros share the first authorship and contributed equally to this article.
    Funding agencies
    ObjectType-Article-1
    SourceType-Scholarly Journals-1
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  • Descrição: ABSTRACT Background The SNCA gene encoding α‐synuclein (αSyn) is the first gene identified to cause autosomal‐dominant Parkinsonʼs disease (PD). Objective We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences. Methods Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn. Results We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co‐segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation. Conclusion Based on the identification of A30G co‐segregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
  • Editor: Hoboken, USA: John Wiley & Sons, Inc
  • Idioma: Inglês
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