LOSS-OF-FUNCTION MUTATIONS IN UDP-GLUCOSE 6-DEHYDROGENASE CAUSE RECESSIVE DEVELOPMENTAL EPILEPTIC ENCEPHALOPATHY

CELIA LAURELINE AGNES BOSSO-LEFEVRE

Publication

LOSS-OF-FUNCTION MUTATIONS IN UDP-GLUCOSE 6-DEHYDROGENASE CAUSE RECESSIVE DEVELOPMENTAL EPILEPTIC ENCEPHALOPATHY

CELIA LAURELINE AGNES BOSSO-LEFEVRE

Abstract

Developmental epileptic encephalopathies (DEE) are devastating disorders characterized by intractable epileptic seizures and developmental delay. In search for genetic causes for DEE, this study considers UDP-Glucose 6-Dehydrogenase (UGDH), which is a cytosolic oxidoreductase that converts UDP-Glucose (UDP-Glc) to UDP-Glucuronic Acid (UDP-GlcA), a precursor for many biosynthetic pathways, including glycosaminoglycans. Here, we report an allelic series of germline recessive mutations in UGDH in 36 patients from 25 families presenting with DEE associated with severe developmental delay and hypotonia. In this study, by using patients’ primary fibroblasts and biochemical assays, we show that these mutations either impair UGDH stability, oligomerization or enzymatic activity. While mutant ugdh zebrafish did not phenocopy the disease in vivo, patient-derived cerebral organoids recapitulated in vitro the cerebral atrophy found in several patients. Based on these findings, our study defines UGDH as a key player for the production of extracellular matrix components essential to human brain development.