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@ARTICLE{Kagermeier:270812,
      author       = {Kagermeier, Theresa and Hauser, Stefan and Sarieva, Kseniia
                      and Laugwitz, Lucia and Groeschel, Samuel and Janzarik,
                      Wibke G and Yentür, Zeynep and Becker, Katharina and
                      Schöls, Ludger and Kragelöh-Mann, Ingeborg and Mayer,
                      Simone},
      title        = {{H}uman organoid model of pontocerebellar hypoplasia 2a
                      recapitulates brain region-specific size differences.},
      journal      = {Disease models $\&$ mechanisms},
      volume       = {17},
      number       = {7},
      issn         = {1754-8403},
      address      = {Cambridge},
      publisher    = {Company of Biologists Limited},
      reportid     = {DZNE-2024-00902},
      pages        = {dmm050740},
      year         = {2024},
      abstract     = {Pontocerebellar hypoplasia type 2a (PCH2a) is an
                      ultra-rare, autosomal recessive pediatric disorder with
                      limited treatment options. Its anatomical hallmark is
                      hypoplasia of the cerebellum and pons accompanied by
                      progressive microcephaly. A homozygous founder variant in
                      TSEN54, which encodes a tRNA splicing endonuclease (TSEN)
                      complex subunit, is causal. The pathological mechanism of
                      PCH2a remains unknown due to the lack of a model system.
                      Therefore, we developed human models of PCH2a using
                      regionalized neural organoids. We generated induced
                      pluripotent stem cell (iPSC) lines from three males with
                      genetically confirmed PCH2a and subsequently differentiated
                      cerebellar and neocortical organoids. Mirroring clinical
                      neuroimaging findings, PCH2a cerebellar organoids were
                      reduced in size compared to controls starting early in
                      differentiation. Neocortical PCH2a organoids demonstrated
                      milder growth deficits. Although PCH2a cerebellar organoids
                      did not upregulate apoptosis, their stem cell zones showed
                      altered proliferation kinetics, with increased proliferation
                      at day 30 and reduced proliferation at day 50 compared to
                      controls. In summary, we generated a human model of PCH2a,
                      providing the foundation for deciphering brain
                      region-specific disease mechanisms. Our first analyses
                      suggest a neurodevelopmental aspect of PCH2a.},
      keywords     = {Humans / Organoids: pathology / Induced Pluripotent Stem
                      Cells: metabolism / Induced Pluripotent Stem Cells:
                      pathology / Male / Brain: pathology / Cell Differentiation /
                      Cerebellum: abnormalities / Cerebellum: pathology /
                      Olivopontocerebellar Atrophies: pathology /
                      Olivopontocerebellar Atrophies: genetics / Cell
                      Proliferation / Organ Size / Models, Biological / Apoptosis
                      / Cerebellar Diseases / Apoptosis (Other) / Cerebellum
                      (Other) / Differentiation (Other) / Organoid (Other) / PCH2a
                      (Other) / Rare disease (Other)},
      cin          = {AG Schöls / AG Hauser},
      ddc          = {570},
      cid          = {I:(DE-2719)5000005 / I:(DE-2719)1210016},
      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},
      pmc          = {pmc:PMC11552497},
      pubmed       = {pmid:39034883},
      doi          = {10.1242/dmm.050740},
      url          = {https://pub.dzne.de/record/270812},
}