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@ARTICLE{AlAzzani:282952,
      author       = {Al-Azzani, Mohammed and Weber, Sandrina and Ramalingam,
                      Nagendran and Ramón, Maria and Shvachiy, Liana and Mestre,
                      Gonçalo and Zech, Michael and Sicking, Kevin and de Opakua,
                      Alain Ibáñez and Jayanthi, Vidyashree and Amaral, Leslie
                      and Agarwal, Aishwarya and Chandran, Aswathy and Chaves,
                      Susana R and Winkelmann, Juliane and Trenkwalder, Claudia
                      and Schwager, Maike and Pauli, Silke and Dettmer, Ulf and
                      Fernández, Claudio O and Lautenschläger, Janin and
                      Zweckstetter, Markus and Fernandez-Busnadiego, Ruben and
                      Mollenhauer, Brit and Outeiro, Tiago Fleming},
      title        = {{A} {N}ovel α-{S}ynuclein {K}58{N} {M}issense {V}ariant in
                      a {P}atient with {P}arkinson's {D}isease.},
      journal      = {Movement disorders},
      volume       = {40},
      number       = {12},
      issn         = {0885-3185},
      address      = {New York, NY},
      publisher    = {Wiley},
      reportid     = {DZNE-2025-01413},
      pages        = {2732 - 2745},
      year         = {2025},
      abstract     = {Parkinson'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.},
      keywords     = {Humans / alpha-Synuclein: genetics / Parkinson Disease:
                      genetics / Mutation, Missense: genetics / Male / Female /
                      Middle Aged / Exome Sequencing / Pedigree / Parkinson's
                      disease (Other) / genetics (Other) / neurodegeneration
                      (Other) / protein aggregation (Other) / α‐synuclein
                      (Other) / alpha-Synuclein (NLM Chemicals) / SNCA protein,
                      human (NLM Chemicals)},
      cin          = {AG Fischer / AG Zweckstetter},
      ddc          = {610},
      cid          = {I:(DE-2719)1410002 / I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40905240},
      pmc          = {pmc:PMC12710137},
      doi          = {10.1002/mds.70030},
      url          = {https://pub.dzne.de/record/282952},
}