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

Life Sci Alliance. 2024 Jan 18;7(4):e202302288. doi: 10.26508/lsa.202302288. Print 2024 Apr.


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.

MeSH terms

  • Brain / metabolism
  • Esophagus* / abnormalities
  • Humans
  • Hypertelorism*
  • Hypospadias*
  • Induced Pluripotent Stem Cells* / metabolism
  • Microtubule Proteins / chemistry
  • Nuclear Proteins* / genetics
  • Transcription Factors / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Microtubule Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • MID1 protein, human

Supplementary concepts

  • Hypertelorism with esophageal abnormality and hypospadias