Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Dpagt1 Missense Variant Causes Early Degenerative Retinopathy without Myasthenic Syndrome in Mice

Lillian F. Hyde
,
Yang Kong
,
Lihong Zhao
,
Sriganesh Ramachandra Rao
ORCID logo ,
Jieping Wang
,
Lisa Stone
ORCID logo ,
Andrew Njaa
,
Gayle B. Collin
,
Mark P. Krebs
ORCID logo ,
Bo Chang
,
Steven J. Fliesler
ORCID logo ,
Patsy M. Nishina
ORCID logo ,
And Jürgen K. Naggert
* ORCID logo
Version 1 : Received: 29 July 2022 / Approved: 4 August 2022 / Online: 4 August 2022 (07:08:13 CEST)

A peer-reviewed article of this Preprint also exists.

Hyde, L.F.; Kong, Y.; Zhao, L.; Rao, S.R.; Wang, J.; Stone, L.; Njaa, A.; Collin, G.B.; Krebs, M.P.; Chang, B.; Fliesler, S.J.; Nishina, P.M.; Naggert, J.K. A Dpagt1 Missense Variant Causes Degenerative Retinopathy without Myasthenic Syndrome in Mice. Int. J. Mol. Sci. 2022, 23, 12005. Hyde, L.F.; Kong, Y.; Zhao, L.; Rao, S.R.; Wang, J.; Stone, L.; Njaa, A.; Collin, G.B.; Krebs, M.P.; Chang, B.; Fliesler, S.J.; Nishina, P.M.; Naggert, J.K. A Dpagt1 Missense Variant Causes Degenerative Retinopathy without Myasthenic Syndrome in Mice. Int. J. Mol. Sci. 2022, 23, 12005.

Abstract

Congenital Disorders of Glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid linked oligosaccha-rides and their transfer to proteins. CDGs affect multiple organ systems and vary in presentation, even within families. Here we describe a chemically induced mouse mutant, tvrm76, with early onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and as-sociated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. Increased expression of Ddit3, and elevated levels of HSPA5 (BiP) sug-gest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause Myasthenic Syndrome 13 and severe forms of Congenital Disorder of Glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

Keywords

DPAGT1; Congenital Disorders of Glycosylation; sensitized chemical mutagenesis screen; mouse genetics; inherited retinal disease; ER Stress

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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