De novo mutation in <i>RING1</i> with epigenetic effects on neurodevelopment.

Abstract

RING1 is an E3-ubiquitin ligase that is involved in epigenetic control of transcription during development. It is a component of the polycomb repressive complex 1, and its role in that complex is to ubiquitylate histone H2A. In a 13-year-old girl with syndromic neurodevelopmental disabilities, we identified a de novo mutation, RING1 p.R95Q, which alters a conserved arginine residue in the catalytic RING domain. In vitro assays demonstrated that the mutant RING1 retains capacity to catalyze ubiquitin chain formation, but is defective in its ability to ubiquitylate histone H2A in nucleosomes. Consistent with this in vitro effect, cells of the patient showed decreased monoubiquitylation of histone H2A. We modeled the mutant RING1 in <i>Caenorhabditis elegans</i> by editing the comparable amino acid change into <i>spat-3</i>, the suggested <i>RING1</i> ortholog. Animals with either the missense mutation or complete knockout of <i>spat-3</i> were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance. Relevant to our patient, animals heterozygous for either the missense or knockout allele also showed neuronal defects. Our results support three conclusions: mutation of <i>RING1</i> is the likely cause of a human neurodevelopmental syndrome, mutation of <i>RING1</i> can disrupt histone H2A ubiquitylation without disrupting RING1 catalytic activity, and the comparable mutation in <i>C. elegans spat-3</i> both recapitulates the effects on histone H2A ubiquitylation and leads to neurodevelopmental abnormalities. This role for <i>RING1</i> adds to our understanding of the importance of aberrant epigenetic effects as causes of human neurodevelopmental disorders.