Congenital protein hypoglycosylation diseases

Sparks, Susan

doi:10.2147/tacg.s18673

Cited by 5 publications

(2 citation statements)

References 161 publications

(123 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, knockdown of POMT2/tw almost reached the same level of rescue as Dpm1 alone (+45.9% vs. +62.1%), while targeting POMT2 would perturb only O-mannosylation. O-mannosylation affects cadherins, plexins, and alpha-dystroglycan, among other proteins [68], and is associated with multiple CDGs, including POMT2-CDG [69]. Thus, like many other candidate genes identified in our study, care would need to be taken in inhibiting this gene in any potential therapies.…”

Section: Discussionmentioning

confidence: 91%

A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress

et al. 2022

View full text Add to dashboard Cite

Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually causes CDGs. While both in vivo models ostensibly cause cellular stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.

show abstract

Section: Discussionmentioning

confidence: 91%

A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress

et al. 2022

View full text Add to dashboard Cite

show abstract

“…For example, knockdown of POMT2/tw almost reached the same level of rescue as Dpm1 alone (+45.9% vs. +62.1%), while targeting POMT2 would perturb only O-mannosylation. O-mannosylation affects cadherins, plexins, and alpha dystrophin, among other proteins 46 , and is associated with multiple CDGs, including POMT2-CDG 47 . Thus, like many other candidate genes identified in our study, care would need to be taken in inhibiting this gene in any potential therapies.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress

Dalton

Viswanatha

Brathwaite

et al. 2021

Preprint

View full text Add to dashboard Cite

Partial loss-of-function mutations in glycosylation pathways underlie a set of rare diseases called Congenital Disorders of Glycosylation (CDGs). In particular, DPAGT1-CDG is caused by mutations in the gene encoding the first step in N-glycosylation, DPAGT1, and this disorder currently lacks effective therapies. To identify potential therapeutic targets for DPAGT1-CDG, we performed CRISPR knockout screens in Drosophila cells for genes associated with better survival and glycoprotein levels under DPAGT1 inhibition. We identified hundreds of candidate genes that may be of therapeutic benefit. Intriguingly, inhibition of the mannosyltransferase Dpm1, or its downstream glycosylation pathways, could rescue two in vivo models of DPAGT1 inhibition and ER stress, even though impairment of these pathways alone usually cause CDGs. While both in vivo models ostensibly cause ER stress (through DPAGT1 inhibition or a misfolded protein), we found a novel difference in fructose metabolism that may indicate glycolysis as a modulator of DPAGT1-CDG. Our results provide new therapeutic targets for DPAGT1-CDG, include the unique finding of Dpm1-related pathways rescuing DPAGT1 inhibition, and reveal a novel interaction between fructose metabolism and ER stress.

show abstract

Setting the stage for universal pharmacological targeting of the glycocalyx

Almahayni¹,

Möckl²

2023

The Cardiovascular Glycocalyx in Health and Disease

View full text Add to dashboard Cite

Congenital protein hypoglycosylation diseases

Cited by 5 publications

References 161 publications

A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress

A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress

A genome-wide CRISPR screen identifies the glycosylation enzyme DPM1 as a modifier of DPAGT1 deficiency and ER stress

Setting the stage for universal pharmacological targeting of the glycocalyx

Contact Info

Product

Resources

About