A novelde novoFEM1C variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia

Abstract

AbstractThe principal component of the protein homeostasis network is the ubiquitin-proteasome system. Ubiquitination is mediated by an enzymatic cascade involving, i.e., E3 ubiquitin ligases, many of which belong to the cullin-RING ligases family. Genetic defects in the ubiquitin-proteasome system components, including cullin-RING ligases, are known causes of neurodevelopmental disorders. Using exome sequencing to diagnose a pediatric patient with developmental delay, pyramidal signs, and limb ataxia, we identified ade novomissense variant c.376G>C; p.(Asp126His) in theFEM1Cgene encoding a cullin-RING ligase substrate receptor. This variant alters a conserved amino acid located within a highly constrained coding region and is predicted as pathogenic by mostin silicotools. In addition, ade novo FEM1Cmutation of the same residue p.(Asp126Val) was associated with an undiagnosed developmental disorder, and the relevant variant (FEM1CAsp126Ala) was found to be functionally compromisedin vitro. Our computational analysis showed that FEM1CAsp126Hishampers protein substrate binding. To further assess its pathogenicity, we used the nematodeCaenorhabditis elegans. We found that the FEM-1Asp133Hisanimals (expressing variant homologous to theFEM1Cp.(Asp126Val)) had normal muscle architecture yet impaired mobility. Mutant worms were sensitive to the acetylcholinesterase inhibitor aldicarb but not levamisole (acetylcholine receptor agonist), showing that their disabled locomotion is caused by synaptic abnormalities and not muscle dysfunction. In conclusion, we provide the first evidence from an animal model suggesting that a mutation in the evolutionarily conserved FEM1C Asp126 position causes a neurodevelopmental disorder in humans.