Congenital myasthenic syndrome due to <scp>DPAGT</scp>1 mutations mimicking congenital myopathy in an Irish family

Bogdanova-Mihaylova, Petya; Murphy, Raymond P.; Alexander, Michael; McHugh, John; Foley, A. Reghan; Brett, Francesca; Murphy, S. M.

doi:10.1111/ene.13532

Cited by 5 publications

(7 citation statements)

References 6 publications

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“…In clinics, many patients bearing mutations in DPAGT1 manifest multiple neurological symptoms [34][35][36][37]. Previous studies have primarily focused on the muscular presentations while eye symptoms are rarely addressed [38][39][40][41]. In this study, we found that the Dpagt1 tvrm76 model recapitulates the retinal degeneration found in some human patients and enables researchers to better probe the pathogenesis of degenerative changes in retina caused by DPAGT1 mutations.…”

Section: Discussionmentioning

confidence: 63%

“…Nevertheless, our results demonstrate that Dpagt1 mutations exist that primarily present with an eye phenotype with minimal muscle involvement. It is possible that the observed phenotype depends on a combination of a specific allele and genetic background modifiers, especially since variation in disease severity has been observed in human patients [41,43,46].…”

Section: Discussionmentioning

confidence: 99%

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

Hyde¹,

Yang²,

Zhao³

et al. 2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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

Hyde¹,

Yang²,

Zhao³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In clinics, many patients bearing mutations in DPAGT1 manifest multiple neurological symptoms [ 43 , 44 , 45 , 46 ]. Previous studies have primarily focused on the muscular presentations, while eye symptoms are rarely addressed [ 47 , 48 , 49 , 50 ]. In this study, we found that the Dpagt1 tvrm76 model recapitulates the retinal degeneration found in some human patients and enables researchers to better probe the pathogenesis of degenerative changes in the retina caused by DPAGT1 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, our results demonstrate that Dpagt1 mutations exist which primarily present with an eye phenotype with minimal muscle involvement. It is possible that the observed phenotype depends on a combination of a specific allele and genetic background modifiers, especially since a variation in disease severity has been observed in human patients [ 50 , 52 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

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

Hyde

Kong

Zhao

et al. 2022

IJMS

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Congenital disorders of glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid-linked oligosaccharides and their transfer to proteins. CDGs usually affect multiple organ systems and vary in presentation, even within families. There is currently no cure, and treatment is aimed at ameliorating symptoms and improving quality of life. Here, we describe a chemically induced mouse mutant, tvrm76, with early-onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and associated 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. This represents the first viable animal model of a Dpagt1 mutation and a novel phenotype for a CDG. The increased expression of Ddit3, and elevated levels of HSPA5 (BiP) suggest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with the induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause myasthenic syndrome-13 and severe forms of a 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.

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“…GFPT1 -CMS has been reported in 17 original articles since 2011 [ 18 , 19 , 20 , 45 , 135 , 140 , 274 , 390 , 392 , 393 , 394 ]. DPAGT1 -CMS [ 21 , 395 , 396 , 397 , 398 ] and GMPPB -CMS [ 25 , 29 , 140 , 141 , 274 , 399 , 400 ] have been reported in five and nine original articles, respectively. ALG2 -CMS has been reported in 9 patients in 4 pedigrees since 2013 [ 24 , 401 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Ohno

Ohkawara

Shen

et al. 2023

IJMS

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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

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Congenital myasthenic syndrome due to DPAGT1 mutations mimicking congenital myopathy in an Irish family

Cited by 5 publications

References 6 publications

A <i>Dpagt1</i> Missense Variant Causes Early Degenerative Retinopathy without Myasthenic Syndrome in Mice

A <i>Dpagt1</i> Missense Variant Causes Early Degenerative Retinopathy without Myasthenic Syndrome in Mice

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

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

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