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

Area of Science:

• Developmental Biology
• Genetics
• Neuroscience

Background:

• Opitz BBB/G syndrome (OS) is an X-linked monogenic disorder.
• Pathogenic variants in the MID1 gene cause OS, with most affecting the locus except the N-terminal RING domain.

Purpose of the Study:

• Investigate the role of MID1 isoforms containing the N-terminal RING domain in human brain development.
• Determine the impact of lacking MID1's E3 ubiquitin ligase activity on embryonic patterning.

Main Methods:

• Utilized genome-edited human induced pluripotent stem cell lines.
• Generated and analyzed human brain organoids with specific MID1 gene modifications.
• Performed transcriptome analysis to identify early molecular changes.

Main Results:

• Absence of MID1 isoforms with the RING domain caused severe patterning defects in brain organoids.
• Observed a significant neurogenic deficit, reduced neural tissue, and increased choroid plexus-like structures.
• Transcriptome data revealed early deregulation of patterning pathways preceding neural induction.

Conclusions:

• The N-terminal RING domain of MID1 is crucial for proper human brain patterning during early development.
• Distinct mechanisms underlie patterning defects when the RING domain is absent compared to full gene knockout.
• This may explain why pathogenic variants in the MID1 RING domain are not observed in OS patients.