Functional Characterization of Loss of RNF43 Reveals Neuronal Defects in a Caenorhabditis elegans Model.

Ring finger protein 43 (RNF43) encodes a transmembrane E3 ubiquitin ligase that negatively regulates canonical Wnt signaling and is classically associated with serrated polyposis syndrome and colorectal cancer. In this study, regarding a homozygous truncating RNF43 variant (NM_001305545.1:c.1906C>T; p.Gln636Ter) in a patient segregating with a severe neurodevelopmental phenotype characterized by developmental delay, neonatal hypotonia, recurrent seizures, progressive microcephaly, and bilateral optic atrophy, the loss of polarity defective 1 (plr-1), an ortholog of RNF43, was modeled in Caenorhabditis elegans and the phenotype was primarily characterized. The results demonstrated that loss of the plr-1 disrupted gamma aminobutyric acid (GABA)ergic axon organization, reduced locomotor speed calculated from 60 s recordings, and altered developmental growth. These findings expand the phenotypic spectrum of RNF43 and support a dosage-dependent developmental role.