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

• Verfasst von: Frank, Sarah [VerfasserIn]
• Verfasst von: Gabassi, Elisa [VerfasserIn]
• Verfasst von: Käseberg, Stephan [VerfasserIn]
• Verfasst von: Bertin, Marco [VerfasserIn]
• Verfasst von: Zografidou, Lea [VerfasserIn]
• Verfasst von: Pfeiffer, Daniela [VerfasserIn]
• Verfasst von: Brennenstuhl, Heiko [VerfasserIn]
• Verfasst von: Falk, Sven [VerfasserIn]
• Verfasst von: Karow, Marisa [VerfasserIn]
• Verfasst von: Schweiger, Susann [VerfasserIn]
• Titel: Absence of the RING domain in MID1 results in patterning defects in the developing human brain
• Verf.angabe: Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, Susann Schweiger
• E-Jahr: 2024
• Jahr: April 2024
• Umfang: 14 S.
• Illustrationen: Illustrationen
• Fussnoten: Online veröffentlicht: 18. Januar 2024 ; Gesehen am 11.06.2024
• Titel Quelle: Enthalten in: Life science alliance
• Ort Quelle: Heidelberg : EMBO Press, 2018
• Jahr Quelle: 2024
• Band/Heft Quelle: 7(2024), 4 vom: Apr., Artikel-ID e202302288, Seite 1-14
• ISSN Quelle: 2575-1077
• DOI: doi:10.26508/lsa.202302288
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1891052128

Abstract

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.