A novel de novo FEM1C variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia

The principal component of the protein homeostasis network is the ubiquitin-proteasome system (UPS). Genetic defects in this system are known causes of neurodevelopmental disorders. Using exome sequencing to diagnose a pediatric patient with developmental delay, pyramidal signs, and limb ataxia, we identified a de novo missense variant c.376G>C; p.(Asp126His) in the FEM1C gene encoding a cullin-RING ligase substrate receptor – protein operating within the UPS. This variant alters a conserved amino acid and is predicted as pathogenic by most in silico tools. In addition, a de novo FEM1C mutation of the same residue p.(Asp126Val) was associated with an undiagnosed developmental disorder, and the relevant variant (FEM1CAsp126Ala) was found to be functionally compromised in vitro. The aim of the study was to investigate in silico and in vivo the linkage of Asp126His mutation in ubiquitin ligase FEM1C with an unknown neurodevelopmental disorder developed in a pediatric patient. Our computational analysis showed that FEM1CAsp126His hampers protein substrate binding. To further assess its pathogenicity, we used the nematode Caenorhabditis elegans. We found that the FEM-1Asp133His animals (expressing variant homologous to the FEM1C p.(Asp126Val)) had normal muscle architecture yet impaired mobility. Mutant worms were sensitive to the acetylcholinesterase inhibitor aldicarb but not levamisole 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 conserved FEM1C Asp126 position causes a neurodevelopmental disorder in humans.---The deposited data are the results of protein-peptide docking using AlphaFold2 and measured features of C. elegans movements in wild-type and mutant worms.