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@PHDTHESIS{Groten:1019979,
      author       = {Groten, Natalie},
      othercontributors = {Kurth, Ingo and Lampert, Angelika},
      title        = {{A}uswirkung einer bislang unbekannten {D}eletionsmutation
                      des {S}pleißfaktors {SRRM}4 auf die {S}ynthese der
                      neuronalen {I}soform von {P}rotrudin},
      school       = {Rheinisch-Westfälische Technische Hochschule Aachen},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2025-08691},
      pages        = {1 Online-Ressource : Illustrationen},
      year         = {2025},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, Rheinisch-Westfälische Technische
                      Hochschule Aachen, 2025},
      abstract     = {This dissertation deals with the case of a patient with a
                      neuronal developmental disorder of unclear origin. In the
                      genetic analysis, a variant in the SRRM4 gene was identified
                      through Whole Exome Sequencing, which was bioinformatically
                      assessed as potentially disease-causing. This mutation
                      occurs in the splice donor sequence behind exon 5 and leads
                      to a complete deletion of this exon at the mRNA level. SRRM4
                      is a neuronal splice factor that regulates the inclusion of
                      various microexons in mRNA through alternative splicing,
                      allowing for the formation of specific neuronal protein
                      isoforms. In the case of the membrane protein
                      Protrudin/ZFYVE27, SRRM4 dysfunction results in the
                      inability to include the microexon L, which characterizes
                      the neuronal isoform, in the mRNA. The absence of the
                      neuronal Protrudin isoform has been shown in mouse models to
                      impair neurogenesis in previous studies. The aim of this
                      work was to further assess the impact of exon 5 deletion on
                      the functionality of the splice factor SRRM4 through
                      molecular and cell biological methods. Experimentally, the
                      SRRM4-supported Protrudin-L production in HeLa cells was
                      measured as a marker of splicing function, using qPCR
                      quantification. The retention of microexon L in ZFYVE27
                      transcripts was observed separately for wild-type SRRM4 and
                      $SRRM4_del.The$ results showed no reduced amount of
                      Protrudin-L in cells with the $SRRM4_del$ construct compared
                      to wild-type, indicating that the mutated splice factor
                      appears to function normally. The deletion of exon 5 does
                      not seem to cause a pathogenic dysfunction. Therefore, the
                      patient's phenotype cannot be sufficiently explained by the
                      SRRM4 mutation investigated in this study. However, further
                      experiments, such as those on neurons, could in the future
                      provide a better replication of neuronal splicing,
                      potentially leading to a revision of the mutation's
                      pathogenic assessment.},
      cin          = {924610},
      ddc          = {610},
      cid          = {$I:(DE-82)525000-2_20140620$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2025-08691},
      url          = {https://publications.rwth-aachen.de/record/1019979},
}