{Reference Type}: Journal Article
{Title}: Absence of the RING domain in MID1 results in patterning defects in the developing human brain.
{Author}: Frank S;Gabassi E;Käseberg S;Bertin M;Zografidou L;Pfeiffer D;Brennenstuhl H;Falk S;Karow M;Schweiger S;
{Journal}: Life Sci Alliance
{Volume}: 7
{Issue}: 4
{Year}: 2024 Apr
{Factor}: 5.781
{DOI}: 10.26508/lsa.202302288
{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.