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@ARTICLE{Mengel:155599,
      author       = {Mengel, David and Traschuetz, Andreas and Reich, Selina and
                      Leyva, Alejandra and Bender, Friedemann and Hauser, Stefan
                      and Haack, Tobias B and Synofzik, Matthis},
      title        = {{A} de novo {STUB}1 variant associated with an early
                      adult-onset multisystemic ataxia phenotype.},
      journal      = {Journal of neurology},
      volume       = {268},
      number       = {10},
      issn         = {0340-5354},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DZNE-2021-00767},
      pages        = {3845-3851},
      year         = {2021},
      note         = {ISSN 1432-1459 not unique: **2 hits**.},
      abstract     = {Biallelic STUB1 variants are a well-established cause of
                      autosomal-recessive early-onset multisystemic ataxia
                      (SCAR16). Evidence for STUB1 variants causing
                      autosomal-dominant ataxia (SCA48) so far largely relies on
                      segregation data in larger families. Presenting the first de
                      novo occurrence of a heterozygous STUB1 variant, we here
                      present additional qualitative evidence for STUB1-disease as
                      an autosomal-dominant disorder.Whole exome sequencing on an
                      index patient with sporadic early-onset ataxia, followed by
                      Sanger sequencing in all family members, was used to
                      identify causative variants as well as to rule out
                      alternative genetic hits and intronic STUB1 variants. STUB1
                      mRNA and protein levels in PBMCs in all family members were
                      analysed using qRT-PCR and Western Blot.A previously
                      unreported start-lost loss-of-function variant c.3G>A in the
                      start codon of STUB1 was identified in the index case,
                      occurring de novo and without evidence for a second
                      (potentially missed) variant (e.g., intronic or copy number)
                      in STUB1. The patient showed an early adult-onset
                      multisystemic ataxia complicated by spastic gait disorder,
                      distal myoclonus and cognitive dysfunction, thus closely
                      mirroring the systems affected in autosomal-recessive
                      STUB1-associated disease. In line with the predicted
                      start-lost effect of the variant, functional investigations
                      demonstrated markedly reduced STUB1 protein expression in
                      PBMCs, whereas mRNA levels were intact.De novo occurrence of
                      the loss-of-function STUB1 variant in our case with
                      multisystemic ataxia provides a qualitatively additional
                      line of evidence for STUB1-disease as an autosomal-dominant
                      disorder, in which the same neurological systems are
                      affected as in its autosomal-recessive counterpart.
                      Moreover, this finding adds support for loss-of-function as
                      a mechanism underlying autosomal-dominant STUB1-disease,
                      thus mirroring its autosomal-recessive counterpart also in
                      terms of the underlying mutational mechanism.},
      keywords     = {Adult / Ataxia: genetics / Cerebellar Ataxia / Humans /
                      Pedigree / Phenotype / Spinocerebellar Ataxias /
                      Ubiquitin-Protein Ligases: genetics / Ataxia (Other) / CHIP
                      (Other) / Dominant (Other) / Early-onset ataxia (Other) /
                      SCA48 (Other) / STUB1 (Other)},
      cin          = {AG Gasser 1 / AG Synofzik / AG Schöls},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000063 /
                      I:(DE-2719)5000005},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC8463406},
      pubmed       = {pmid:33811518},
      doi          = {10.1007/s00415-021-10524-7},
      url          = {https://pub.dzne.de/record/155599},
}