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Frank, Sarah [Author]; Gabassi, Elisa [Author]; Käseberg, Stephan [Author]; Bertin, Marco [Author]; Zografidou, Lea [Author]; Pfeiffer, Daniela [Author]; Brennenstuhl, Heiko [Author]; Falk, Sven [Author]; Karow, Marisa [Author]; Schweiger, Susann [Author]

Absence of the RING domain in MID1 results in patterning defects in the developing human brain

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  • Media type: E-Article
  • Title: Absence of the RING domain in MID1 results in patterning defects in the developing human brain
  • Contributor: Frank, Sarah [Author]; Gabassi, Elisa [Author]; Käseberg, Stephan [Author]; Bertin, Marco [Author]; Zografidou, Lea [Author]; Pfeiffer, Daniela [Author]; Brennenstuhl, Heiko [Author]; Falk, Sven [Author]; Karow, Marisa [Author]; Schweiger, Susann [Author]
  • Published: April 2024
  • Published in: Life science alliance ; 7(2024), 4 vom: Apr., Artikel-ID e202302288, Seite 1-14
  • Language: English
  • DOI: 10.26508/lsa.202302288
  • Identifier:
  • Origination:
  • Footnote: Online veröffentlicht: 18. Januar 2024
  • Description: The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1. Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids. We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures. Transcriptome analyses revealed a deregulation of patterning pathways very early on, even preceding neural induction. Notably, the observed phenotypes starkly contrast with those observed in MID1 full-knockout organoids, indicating the presence of a distinct mechanism that underlies the patterning defects. The severity and early onset of these phenotypes could potentially account for the absence of patients carrying pathogenic variants in exon 1 of the MID1 gene coding for the N-terminal RING domain.
  • Access State: Open Access