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@ARTICLE{Minnerop:834448,
      author       = {Minnerop, Martina and Kurzwelly, Delia and Wagner, Holger
                      and Soehn, Anne S and Reichbauer, Jennifer and Tao, Feifei
                      and Rattay, Tim W and Peitz, Michael and Rehbach, Kristina
                      and Giorgetti, Alejandro and Pyle, Angela and Thiele, Holger
                      and Altmüller, Janine and Timmann, Dagmar and Karaca, Ilker
                      and Lennarz, Martina and Baets, Jonathan and Hengel, Holger
                      and Synofzik, Matthis and Atasu, Burcu and Feely, Shawna and
                      Kennerson, Marina and Stendel, Claudia and Lindig, Tobias
                      and Gonzalez, Michael A and Stirnberg, Rüdiger and Sturm,
                      Marc and Roeske, Sandra and Jung, Johanna and Bauer, Peter
                      and Lohmann, Ebba and Herms, Stefan and Heilmann-Heimbach,
                      Stefanie and Nicholson, Garth and Mahanjah, Muhammad and
                      Sharkia, Rajech and Carloni, Paolo and Brüstle, Oliver and
                      Klopstock, Thomas and Mathews, Katherine D and Shy, Michael
                      E and de Jonghe, Peter and Chinnery, Patrick F and Horvath,
                      Rita and Kohlhase, Jürgen and Schmitt, Ina and Wolf,
                      Michael and Greschus, Susanne and Amunts, Katrin and Maier,
                      Wolfgang and Schöls, Ludger and Nürnberg, Peter and
                      Zuchner, Stephan and Klockgether, Thomas and Ramirez,
                      Alfredo and Schüle, Rebecca},
      title        = {{H}ypomorphic mutations in {POLR}3{A} are a frequent cause
                      of sporadic and recessive spastic ataxia.},
      journal      = {Brain},
      volume       = {140},
      number       = {6},
      issn         = {1460-2156},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2017-04404},
      pages        = {1561 - 1578},
      year         = {2017},
      abstract     = {Despite extensive efforts, half of patients with rare
                      movement disorders such as hereditary spastic paraplegias
                      and cerebellar ataxias remain genetically unexplained,
                      implicating novel genes and unrecognized mutations in known
                      genes. Non-coding DNA variants are suspected to account for
                      a substantial part of undiscovered causes of rare diseases.
                      Here we identified mutations located deep in introns of
                      POLR3A to be a frequent cause of hereditary spastic
                      paraplegia and cerebellar ataxia. First, whole-exome
                      sequencing findings in a recessive spastic ataxia family
                      turned our attention to intronic variants in POLR3A, a gene
                      previously associated with hypomyelinating leukodystrophy
                      type 7. Next, we screened a cohort of hereditary spastic
                      paraplegia and cerebellar ataxia cases (n = 618) for
                      mutations in POLR3A and identified compound heterozygous
                      POLR3A mutations in $∼3.1\%$ of index cases.
                      Interestingly, $>80\%$ of POLR3A mutation carriers presented
                      the same deep-intronic mutation (c.1909+22G>A), which
                      activates a cryptic splice site in a tissue and stage of
                      development-specific manner and leads to a novel distinct
                      and uniform phenotype. The phenotype is characterized by
                      adolescent-onset progressive spastic ataxia with frequent
                      occurrence of tremor, involvement of the central sensory
                      tracts and dental problems (hypodontia, early onset of
                      severe and aggressive periodontal disease). Instead of the
                      typical hypomyelination magnetic resonance imaging pattern
                      associated with classical POLR3A mutations, cases carrying
                      c.1909+22G>A demonstrated hyperintensities along the
                      superior cerebellar peduncles. These hyperintensities may
                      represent the structural correlate to the cerebellar
                      symptoms observed in these patients. The associated
                      c.1909+22G>A variant was significantly enriched in 1139
                      cases with spastic ataxia-related phenotypes as compared to
                      unrelated neurological and non-neurological phenotypes and
                      healthy controls (P = 1.3 × 10-4). In this study we
                      demonstrate that (i) autosomal-recessive mutations in POLR3A
                      are a frequent cause of hereditary spastic ataxias,
                      accounting for about $3\%$ of hitherto genetically
                      unclassified autosomal recessive and sporadic cases; and
                      (ii) hypomyelination is frequently absent in POLR3A-related
                      syndromes, especially when intronic mutations are present,
                      and thus can no longer be considered as the unifying feature
                      of POLR3A disease. Furthermore, our results demonstrate that
                      substantial progress in revealing the causes of Mendelian
                      diseases can be made by exploring the non-coding sequences
                      of the human genome.},
      cin          = {INM-1 / INM-9 / IAS-5},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-1-20090406 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)IAS-5-20120330},
      pnm          = {571 - Connectivity and Activity (POF3-571)},
      pid          = {G:(DE-HGF)POF3-571},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28459997},
      UT           = {WOS:000402726600013},
      doi          = {10.1093/brain/awx095},
      url          = {https://juser.fz-juelich.de/record/834448},
}