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

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-termi...

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Main Authors: 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)
Format: Article (Journal)
Language:English
Published: April 2024
In: Life science alliance
Year: 2024, Volume: 7, Issue: 4, Pages: 1-14
ISSN:2575-1077
DOI:10.26508/lsa.202302288
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.26508/lsa.202302288
Verlag, kostenfrei, Volltext: https://www.life-science-alliance.org/content/7/4/e202302288
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Author Notes:Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, Susann Schweiger
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Summary: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.
Item Description:Online veröffentlicht: 18. Januar 2024
Gesehen am 11.06.2024
Physical Description:Online Resource
ISSN:2575-1077
DOI:10.26508/lsa.202302288

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