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@ARTICLE{Hengel:280232,
      author       = {Hengel, Holger and Hannan, Shabab-Bin and Reich, Selina and
                      Beijer, Danique and Roller, Johanna Rosa and Gilsbach, Bernd
                      K and Gloeckner, Christian Johannes and Greene, Daniel and
                      Timmann, Dagmar and Depienne, Christel and Mumford, Andrew
                      and O'Driscoll, Mary and Nemeth, Andrea H and Lundberg,
                      Julie and Rodan, Lance H and Bruel, Ange-Line and Delanne,
                      Julian and Deconinck, Tine and Baets, Jonathan and Gan-Or,
                      Ziv and Rouleau, Guy and Suchowersky, Oksana and Estiar,
                      Mehrdad A and Reich, Stephen and Toro, Camilo and Züchner,
                      Stephan and Hazan, Jamilé and Pétursson, Hjörvar and
                      Harmuth, Florian and Bauer, Claudia and Bauer, Peter and
                      Turro, Ernest and Lambright, David and Schöls, Ludger and
                      Synofzik, Matthis},
      title        = {{H}eterozygous {RAB}3{A} variants cause cerebellar ataxia
                      by a partial loss-of-function mechanism.},
      journal      = {Brain},
      volume       = {148},
      number       = {8},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2025-00910},
      pages        = {2812 - 2826},
      year         = {2025},
      abstract     = {RAB3A encodes a small GTP-binding protein that is abundant
                      in brain synaptic vesicles and crucial for the release of
                      neurotransmitters and synaptic plasticity. Here, we
                      identified RAB3A as a candidate gene for autosomal dominant
                      cerebellar ataxia by two independent approaches: linkage in
                      a large dominant ataxia family and, in parallel, an
                      untargeted computational genetic association approach,
                      analysing the 100 000 Genomes Project datasets. To validate
                      the role of RAB3A in ataxia, we next screened large rare
                      disease databases for rare heterozygous RAB3A variants in
                      probands with ataxia features. In total, we identified 18
                      individuals from 10 unrelated families all sharing a
                      cerebellar ataxia phenotype. Notably, 9 of the 10 families
                      carried a recurrent variant in RAB3A, p.Arg83Trp, including
                      one de novo occurrence. In addition, our screening revealed
                      three families with a neurodevelopmental phenotype and three
                      unique RAB3A variants, which were either de novo or
                      loss-of-function variants. In line with the different RAB3A
                      variant types, protein domains and predicted functional
                      consequences, a comprehensive set of complementary methods
                      was used to characterize the identified variants
                      functionally. As expected, GTPase-activating protein
                      (GAP)-dependent GTP hydrolysis was reduced for those two
                      missense variants located in the GAP-binding domain of RAB3A
                      (Arg83Trp and Tyr91Cys). In a Drosophila Rab3
                      loss-of-function model, these two missense variants also
                      failed to rescue a synaptic phenotype. Overexpression of
                      Rab3 variants in Drosophila wild-type background did not
                      cause an obvious phenotype, making a dominant negative
                      effect of these variants unlikely. Lastly, exploring
                      interactors of RAB3A variants by using
                      co-immunoprecipitation and mass spectrometry showed
                      differential changes in variant-specific interactions with
                      known RAB3A key regulatory and effector proteins. In sum,
                      our results establish RAB3A as a neurological disease gene.
                      It represents an autosomal dominant gene for cerebellar
                      ataxia with different variants associated with disease,
                      including the frequent reoccurring variant p.Arg83Trp. Our
                      study sheds light on the variant-specific interactome of
                      RAB3A. Finally, we suggest an association of RAB3A with a
                      neurodevelopmental phenotype, as reported for variants in
                      several RAB3A interaction partners and as seen in
                      Rab3A-deficent mice, although this possible association
                      warrants further investigation by future studies.},
      keywords     = {Humans / rab3A GTP-Binding Protein: genetics / rab3A
                      GTP-Binding Protein: metabolism / Cerebellar Ataxia:
                      genetics / Animals / Male / Female / Pedigree / Middle Aged
                      / Heterozygote / Adult / Loss of Function Mutation: genetics
                      / Phenotype / Bayesian statistical genetic association
                      (Other) / GTPase (Other) / Rareservoir (Other) / genome
                      sequencing (Other) / neurodevelopmental disorder (Other) /
                      neurogenetic disease (Other) / rab3A GTP-Binding Protein
                      (NLM Chemicals)},
      cin          = {AG Gasser / AG Schöls / AG Gloeckner},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000005 /
                      I:(DE-2719)1210007},
      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:40166812},
      pmc          = {pmc:PMC12316009},
      doi          = {10.1093/brain/awaf111},
      url          = {https://pub.dzne.de/record/280232},
}