2020 journal article

Cite it

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

NATURE COMMUNICATIONS, 11(1).

By: H. Hengel ^*, C. Bosso-Lefevre ^*, G. Grady ⁿ, E. Szenker-Ravi ^*, H. Li ^*, S. Pierce ^*, E. Lebigot ^*, T. Tan ^* ...and 77 other authors, including 1 NC State author, M. Eio^*, G. Narayanan^*, K. Utami ^*, M. Yau^*, N. Handal^*, W. Deigendesch^*, R. Keimer, H. Marzouqa^*, M. Gunay-Aygun ^*, M. Muriello ^*, H. Verhelst ^*, S. Weckhuysen ^*, S. Mahida ^*, S. Naidu^*, T. Thomas ^*, J. Lim ^*, E. Tan^*, D. Haye ^*, M. Willemsen ^*, R. Oegema ^*, W. Mitchell ^*, T. Pierson ^*, M. Andrews ^*, M. Willing^*, L. Rodan ^*, T. Barakat ^*, M. Slegtenhorst^*, R. Gavrilova ^*, D. Martinelli ^*, T. Gilboa ^*, A. Tamim ^*, M. Hashem ^*, M. AlSayed ^*, M. Abdulrahim ^*, M. Al-Owain^*, A. Awaji^*, A. Mahmoud ^*, E. Faqeih ^*, A. Al Asmari^*, S. Algain ^*, L. Jad^*, H. Aldhalaan ^*, I. Helbig ^*, D. Koolen ^*, A. Riess^*, I. Kraegeloh-Mann^*, P. Bauer ^*, S. Gulsuner ^*, H. Stamberger ^*, A. Ng ^*, S. Tang ^*, S. Tohari^*, B. Keren ^*, L. Schultz-Rogers ^*, E. Klee ^*, S. Barresi ^*, M. Tartaglia ^*, H. Mor-Shaked ^*, S. Maddirevula ^*, A. Begtrup, A. Telegrafi, R. Pfundt^*, R. Schuele, B. Ciruna ^*, C. Bonnard ^*, M. Pouladi ^*, J. Stewart ^*, A. Claridge-Chang ^*, D. Lefeber ^*, F. Alkuraya ^*, A. Mathuru ^*, B. Venkatesh ^*, J. Barycki ⁿ, M. Simpson ⁿ, S. Jamuar ^*, L. Schoels, B. Reversade ^*(hide authors)

MeSH headings : Adolescent; Alleles; Animals; Child; Child, Preschool; Epilepsy / genetics; Female; Genes, Recessive; Humans; Infant; Kinetics; Loss of Function Mutation / genetics; Male; Organoids / pathology; Oxidoreductases / chemistry; Oxidoreductases / genetics; Pedigree; Protein Domains; Syndrome; Uridine Diphosphate Glucose Dehydrogenase / genetics; Zebrafish

TL;DR: Biallelic variants in the gene encoding UDP-Glucose 6-Dehydrogenase (UGDH) in individuals affected by developmental epileptic encephalopathies that impair UGDH stability, oligomerization, or enzymatic activity in vitro are reported. (via Semantic Scholar)

10.1038/s41467-020-14360-7

Find Text @ NCSU

open access via www.nature.com (publisher PDF)

PubMed

UN Sustainable Development Goal Categories

3. Good Health and Well-being (Web of Science)

Source: Web Of Science

Added: July 20, 2020

AbstractDevelopmental 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.