Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Abstract

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort

“…Importantly, in three cases the diagnosis was reached before published evidence was available, based on internal data analysis of patients in our data repository. These cases presented with variants in NKX6 -2 [ 25 ], PRUNE1 [ 26 ], and UGDH [ 27 ].…”

A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism

“…The mutation was located in exon 8 and belongs to the same exon 8 region in cats that appeared to be duplicated as part of the feline dwarfism SV, a region of the protein known as the central domain. Other more severe LoF mutations have also been identified in UGDH in humans, causing recessive developmental epileptic encephalopathy [ 81 ]. Almost all of these cases were compound heterozygotes with healthy parents, indicating a single functional copy of UGDH is sufficient for healthy development in humans.…”

A Missense Mutation in the UGDH Gene Is Associated With Developmental Delay and Axial Hypotonia

“…Additionally, it was reported that UGDH polymorphisms were associated with epileptic in Native American population (50). Recently, several germline recessive mutations in the UGDH were associated with developmental epileptic encephalopathies, developmental delay and hypotonia ( Table 1) (51). Further, research using animal models will be crucial for understanding the exact mechanism of UGDH underlying developmental delay.…”