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@ARTICLE{Liu:155632,
author = {Liu, Hui and Koros, Christos and Strohäker, Timo and
Schulte, Claudia and Bozi, Maria and Varvaresos, Stefanos
and Ibáñez de Opakua, Alain and Simitsi, Athina Maria and
Bougea, Anastasia and Voumvourakis, Konstantinos and
Maniati, Matina and Papageorgiou, Sokratis G and Hauser,
Ann-Kathrin and Becker, Stefan and Zweckstetter, Markus and
Stefanis, Leonidas and Gasser, Thomas},
title = {{A} {N}ovel {SNCA} {A}30{G} {M}utation {C}auses {F}amilial
{P}arkinson's {D}isease.},
journal = {Movement disorders},
volume = {36},
number = {7},
issn = {1531-8257},
address = {New York, NY},
publisher = {Wiley},
reportid = {DZNE-2021-00800},
pages = {1624 - 1633},
year = {2021},
abstract = {The SNCA gene encoding α-synuclein (αSyn) is the first
gene identified to cause autosomal-dominant Parkinson's
disease (PD).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.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.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.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.},
keywords = {Founder Effect / Greece / Humans / Mutation: genetics /
Parkinson Disease: genetics / alpha-Synuclein: genetics /
A30G (Other) / Parkinsonʼs disease (Other) / SNCA (Other) /
SNCA protein, human (NLM Chemicals) / alpha-Synuclein (NLM
Chemicals)},
cin = {AG Zweckstetter / AG Berg ; AG Berg / AG Gasser 1},
ddc = {610},
cid = {I:(DE-2719)1410001 / I:(DE-2719)5000055 /
I:(DE-2719)1210000},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:33617693},
doi = {10.1002/mds.28534},
url = {https://pub.dzne.de/record/155632},
}