• Luo-Schoch-Yamamoto syndrome

This report describes Luo-Schoch-Yamamoto syndrome, a newly defined neurodevelopmental syndrome caused by heterozygous mutations in the RNF2 gene. RNF2 (aka RING2) encodes a member of the Polycomb group (PcG) of proteins and acts as a ubiquitin-protein ligase that mediates ubiquitination of histone H2A. There is a single orthologous gene in Drosophila, Sce, for which multiple genetic reagents have been generated including including amorphic alleles, overexpression and RNAi targeting constructs, and alleles caused by insertional mutagenesis. Dmel\Sce is also orthologous to the human RING1 gene.

The human RNF2 gene has not been introduced into flies.

Work in Drosophila addresses the question of whether the newly described de novo missense variants implicated in this disease are loss-of-function mutations. Other evidence supports the premise that RNF2 is a haploinsufficient locus, in which case it would be consistent that the missense variants are loss-of-function mutations. Alternatively, they could have dominant negative effects. Mutations analogous to those in the human gene have been introduced into transgenic copies of the fly Sce gene (see the Disease-Implicated Variants table below). The ability of these constructs to rescue the lethality associated with Sce null genotypes has been assessed; neither variant is able to rescue the lethal phenotype. A third variant at the same site as one of the pathogenic variants was found to be segregating at a low frequency in general populations; tested in the rescue assay, this variant does rescue the lethal phenotype. In a second assay testing for rescue of a heterozygous homeotic phenotype of Sce, one of the disease-implicated variants is able to effect partial rescue and thus may cause a less profound loss of function. This correlates with the less severe phenotype of the individual carrying the corresponding human variant.

[updated Aug. 2021 by FlyBase; FBrf0222196]