A novel de novo FEM1C variant as a potential cause of neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia

Abstract

Maintaining protein homeostasis (proteostasis) requires the degradation of damaged or unwanted proteins and plays a crucial role in cellular function. The principal proteolytic component of the proteostasis network is the ubiquitin-proteasome system (UPS) which orchestrates protein degradation through ubiquitination of appropriate targets. Ubiquitination is mediated by an enzymatic cascade involving, i.e., E3 ubiquitin ligases, many of which belong to the cullin-RING ligases (CRLs) family. Genetic defects of the UPS are known causes of neurodevelopmental disorders, with >60 entities described so far. Using exome sequencing (ES) to diagnose a pediatric patient with global developmental delay, pyramidal signs, and limb ataxia, we identified a de novo missense variant c.376G>C; p.(Asp126His) in the FEM1C gene, which encodes a CRL substrate receptor. The p.(Asp126His) variant, which alters a conserved amino acid (phyloP100way = 7.9), is located within a highly constrained coding region (CCR=98.6) and is predicted to be pathogenic by the majority (13/19) of in silico tools. To further assess its pathogenicity, we employed Caenorhabditis elegans nematode as a disease model. We found that the mutant vs. wild-type worms had impaired mobility as assessed by track length (p=0.0001), turn counts (p=0.0001), and omega bend counts (p=0.038). Furthermore, mutant worms had histologically normal muscle architecture but were sensitive to an acetylcholinesterase inhibitor - aldicarb which indicates that their locomotion defects result from synaptic defects rather than muscle dysfunction. We conclude that the disease in our patient may be the first reported case of a neurodevelopmental disorder caused by the FEM1C genetic defect.