2. Academic Validation
  3. C-terminally clustered UGDH hypomorphic variants reveal subtle mechanisms of cellular and developmental disruption

C-terminally clustered UGDH hypomorphic variants reveal subtle mechanisms of cellular and developmental disruption

  • Matrix Biol. 2026 Jun:146:102011. doi: 10.1016/j.matbio.2026.102011.
Hali Harwood 1,  Brenna M Zimmer 1,  Asher R Utz 1,  Myrrhe Venema 2,  Emily Allego 1,  Sydney S Skirboll 1,  Autumn Harding 1,  Jeffrey R Enders 3,  Sarah Grantham-Hill 4,  Frances Elmslie 4,  Yong-Ru Ly 5,  Antonia Clarke 6,  Maria Xu 7,  Hui Jeen Tan 8,  Karen Stals 9,  Saumya Shekhar Jamuar 10,  Tahsin Stefan Barakat 2,  Thomas M Makris 1,  Joseph J Barycki 11,  Melanie A Simpson 12
Affiliations

Affiliations

  • 1 Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
  • 2 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 3 Molecular Education, Technology and Research Innovation Center, North Carolina State University, Raleigh, NC 27695, USA.
  • 4 South West Thames Centre for Genomics, St George's University Hospitals NHS Foundation Trust, London, UK.
  • 5 Synnovis Biochemical Genetics, Guy's Hospital, London, UK.
  • 6 Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.
  • 7 Manchester Centre for Genomic Medicine, Manchester, UK.
  • 8 Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, UK.
  • 9 Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
  • 10 Genetics service, KK Women's and Children's Hospital, Singapore.
  • 11 Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA; Molecular Education, Technology and Research Innovation Center, North Carolina State University, Raleigh, NC 27695, USA.
  • 12 Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: [email protected].
PMID: 42061477 DOI: 10.1016/j.matbio.2026.102011
Abstract

Jamuar syndrome (Developmental and Epileptic Encephalopathy 84, OMIM# 618792) is a rare autosomal recessive congenital disorder of glycosylation (CDG), caused by variations in the gene encoding UDP-glucose dehydrogenase (UGDH). Although a number of UGDH variants have been functionally characterized, there is an incomplete catalogue of variants and their impacts on development. Here, we present functional data characterizing new missense variants from three unrelated individuals who were D379N homozygous, Y356D homozygous, and compound heterozygous A436G/R442W, respectively. UGDH activity was low to undetectable in patient-derived fibroblasts bearing either UGDH D379N or UGDH A436G/R442W, relative to WT fibroblasts, despite robust UGDH expression in both. Measurement of nucleotide sugar levels revealed a significant decrease in the UGDH product, UDP-glucuronate, and consequent reductions in hyaluronan production, Notch1 levels, and rate of O-and N-linked glycan synthesis, consistent with loss of UGDH activity. These features support the designation of UGDH D379N and UGDH A436G as causative variants in Jamuar Syndrome. We expressed and purified UGDH D379N, A436G, R442W, R443H, and Y356D variants to examine underlying molecular mechanisms. Kinetic properties and structural stability assays selectively revealed significant changes in conformational dynamics that manifested strong effects on endogenous inhibitor binding and product inhibition. The results suggest that alterations to the C-terminal domain impact activity of UGDH in cells by impairing its cofactor exchange rate and diminishing quaternary association. These effects would be maximized at developmental milestones in which hypoxia drives morphological change, since NADH accumulation would then decrease glycosaminoglycan production, with profound developmental consequences.

Keywords

Congenital disorders of glycosylation; Developmental epileptic encephalopathy; Glycosaminoglycan; Hyaluronan; UDP-glucose dehydrogenase; enzyme kinetics.

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