Publications by authors named "T Kozicz"

Core components of the N-glycosylation pathway are known, but the metabolic and post-translational mechanisms regulating this pathway in normal and disease states remain elusive. Using a multi-omic approach in zebrafish, we discovered a mechanism whereby O-GlcNAcylation directly impacts the expression and abundance of two rate-limiting proteins in the N-linked glycosylation pathway. We show in a model of an inherited glycosylation disorder PMM2-CDG, congenital disorders of glycosylation that phosphomannomutase deficiency is associated with increased levels of UDP-GlcNAc and protein O-GlcNAcylation.

View Article and Find Full Text PDF
Article Synopsis
  • Mono-allelic DHDDS variants lead to a range of neurological issues, including seizures, intellectual disabilities, and movement disorders, with symptoms beginning at different ages and progressing variably among patients.
  • A study of 59 patients revealed that while symptoms often start early, the onset and development can differ widely, with some experiencing the full range in childhood and others in adulthood.
  • No clear links were found between symptom onset or progression and factors like patient sex or specific DHDDS variants, but 19% of patients also showed signs of autism spectrum disorder, highlighting its relevance in managing the condition.
View Article and Find Full Text PDF

SRD5A3-CDG is a congenital disorder of glycosylation (CDG) resulting from pathogenic variants in SRD5A3 and follows an autosomal recessive inheritance pattern. The enzyme encoded by SRD5A3, polyprenal reductase, plays a crucial role in synthesizing lipid precursors essential for N-linked glycosylation. Despite insights from functional studies into its enzymatic function, there remains a gap in understanding global changes in patient cells.

View Article and Find Full Text PDF

ALG1-CDG is a rare, clinically variable metabolic disease, caused by the defect of adding the first mannose (Man) to N-acetylglucosamine (GlcNAc)-pyrophosphate (PP)-dolichol to the growing oligosaccharide chain, resulting in impaired N-glycosylation of proteins. N-glycosylation has a key role in functionality, stability, and half-life of most proteins. Therefore, congenital defects of glycosylation typically are multisystem disorders.

View Article and Find Full Text PDF

Phosphomannomutase 2 (PMM2) converts mannose-6-phospahate to mannose-1-phosphate; the substrate for GDP-mannose, a building block of the glycosylation biosynthetic pathway. Pathogenic variants in the PMM2 gene have been shown to be associated with protein hypoglycosylation causing PMM2-congenital disorder of glycosylation (PMM2-CDG). While mannose supplementation improves glycosylation in vitro, but not in vivo, we hypothesized that liposomal delivery of mannose-1-phosphate could increase the stability and delivery of the activated sugar to enter the targeted compartments of cells.

View Article and Find Full Text PDF