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000282952 1001_ $$00000-0003-2864-0854$$aAl-Azzani, Mohammed$$b0
000282952 245__ $$aA Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease.
000282952 260__ $$aNew York, NY$$bWiley$$c2025
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000282952 520__ $$aParkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in SNCA gene, encoding α-synuclein (aSyn), are linked to rare familial forms of PD.Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD.We describe the clinical presentation associated with the novel mutation, together with genetic testing through whole exome sequencing (WES). Furthermore, we conducted extensive biophysical and cellular assays to assess the functional consequences of this novel variant.The patient exhibited typical features of sporadic PD with early onset and a benign disease course. WES showed a novel heterozygous missense variant in SNCA (NM_000345.4, c.174G>C; p.K58N). A positive family history of PD was evident, because both a parent and a grandparent had been diagnosed with PD but were deceased. The patient underwent deep brain stimulation surgery 13 years postdiagnosis, showing stable, long-term improvements in motor symptoms. Biophysical studies demonstrated K58N substitution causes local structural effects, disrupts membrane binding, and enhances aSyn in vitro aggregation. In cellular systems, K58N aSyn produces fewer inclusions per cell and does not form condensates. The variant increases aSyn cytoplasmic distribution and displays aberrant activity-dependent dynamic serine-129 phosphorylation.The clinical presentation associated with the novel K58N aSyn mutation suggests a relatively benign PD course consistent with the phenotypic spectrum of idiopathic PD. Overall, our molecular studies provide novel insight into the biology and pathobiology of aSyn. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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000282952 650_7 $$2Other$$aParkinson's disease
000282952 650_7 $$2Other$$agenetics
000282952 650_7 $$2Other$$aneurodegeneration
000282952 650_7 $$2Other$$aprotein aggregation
000282952 650_7 $$2Other$$aα‐synuclein
000282952 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000282952 650_7 $$2NLM Chemicals$$aSNCA protein, human
000282952 650_2 $$2MeSH$$aHumans
000282952 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000282952 650_2 $$2MeSH$$aParkinson Disease: genetics
000282952 650_2 $$2MeSH$$aMutation, Missense: genetics
000282952 650_2 $$2MeSH$$aMale
000282952 650_2 $$2MeSH$$aFemale
000282952 650_2 $$2MeSH$$aMiddle Aged
000282952 650_2 $$2MeSH$$aExome Sequencing
000282952 650_2 $$2MeSH$$aPedigree
000282952 7001_ $$00000-0001-5713-2141$$aWeber, Sandrina$$b1
000282952 7001_ $$00000-0002-9459-3593$$aRamalingam, Nagendran$$b2
000282952 7001_ $$aRamón, Maria$$b3
000282952 7001_ $$aShvachiy, Liana$$b4
000282952 7001_ $$aMestre, Gonçalo$$b5
000282952 7001_ $$00000-0001-8112-9153$$aZech, Michael$$b6
000282952 7001_ $$aSicking, Kevin$$b7
000282952 7001_ $$0P:(DE-2719)2812657$$ade Opakua, Alain Ibáñez$$b8$$udzne
000282952 7001_ $$aJayanthi, Vidyashree$$b9
000282952 7001_ $$aAmaral, Leslie$$b10
000282952 7001_ $$aAgarwal, Aishwarya$$b11
000282952 7001_ $$aChandran, Aswathy$$b12
000282952 7001_ $$aChaves, Susana R$$b13
000282952 7001_ $$aWinkelmann, Juliane$$b14
000282952 7001_ $$aTrenkwalder, Claudia$$b15
000282952 7001_ $$aSchwager, Maike$$b16
000282952 7001_ $$aPauli, Silke$$b17
000282952 7001_ $$aDettmer, Ulf$$b18
000282952 7001_ $$aFernández, Claudio O$$b19
000282952 7001_ $$aLautenschläger, Janin$$b20
000282952 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b21$$udzne
000282952 7001_ $$aFernandez-Busnadiego, Ruben$$b22
000282952 7001_ $$0P:(DE-2719)9001340$$aMollenhauer, Brit$$b23$$udzne
000282952 7001_ $$0P:(DE-2719)2814138$$aOuteiro, Tiago Fleming$$b24$$eLast author$$udzne
000282952 773__ $$0PERI:(DE-600)2041249-6$$a10.1002/mds.70030$$gVol. 40, no. 12, p. 2732 - 2745$$n12$$p2732 - 2745$$tMovement disorders$$v40$$x0885-3185$$y2025
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