Clinical features in a large Iranian family with a limb-girdle congenital myasthenic syndrome due to a mutation in DPAGT1

Basiri, Keivan; Belaya, Katsiaryna; Liu, Wei Wei; Maxwell, Susan; Sedghi, Maryam; Beeson, David

doi:10.1016/j.nmd.2013.03.003

Cited by 30 publications

(30 citation statements)

References 18 publications

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“…Twenty-five variants have been reported: twenty-one missense variants, three splicing variants and one duplication vari ant [1][2][3][4][5][6][7][8][9][10][11] (www.lovd.nl/DPAGT1). The standard reference sequence indicating reported variants (ENSG00000172269) and a reference for exon numbering (ENST00000354202) can be found at http://www.…”

Section: Mutational Spectrummentioning

confidence: 99%

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Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation

2015

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Section: Mutational Spectrummentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] The frequency and the prevalence of the disease are not known.…”

Section: Analytical Validationmentioning

confidence: 99%

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Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation

2015

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“…10 The neuromuscular transmission defect was attributed to decreased cellular synthesis and export of the hypoglycosylated acetylcholine receptor (AChR) to the postsynaptic membrane.…”

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confidence: 99%

“…10 The neuromuscular transmission defect was attributed to decreased cellular synthesis and export of the hypoglycosylated acetylcholine receptor (AChR) to the postsynaptic membrane. 5 The mean a-bungarotoxin (a-bgt) binding per EP was 11.2 atomoles in 4 patients compared with 13 to 30 atomoles in controls.…”

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confidence: 99%

DPAGT1 myasthenia and myopathy

et al. 2014

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Objective: To investigate patients with DPAGT1 (UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase 1)-associated myasthenic syndrome. Methods:We performed exome and Sanger sequencing, determined glycoprotein expression in patient muscles, assessed pathogenicity of the mutant proteins by examining their expression and enzymatic activity in transfected cells, evaluated structural changes in muscle and the neuromuscular junction, and examined electrophysiologic aspects of neuromuscular transmission in vitro.Results: Patients 1 and 2, 16 and 14 years of age, had progressive fatigable weakness since infancy and are intellectually disabled. Patient 3, a less severely affected brother of patient 1, also has autistic features. Each patient harbors 2 novel heteroallelic mutations in DPAGT1, an enzyme subserving protein N-glycosylation. Patients 1 and 3 harbor Met1Leu, which reduces protein expression, and His375Tyr, which decreases enzyme activity. Patient 2 carries Val264Met, which abolishes enzyme activity, and a synonymous Leu120Leu mutation that markedly augments exon skipping, resulting in some skipped and infrequent nonskipped alleles. Therefore, the nonskipped allele rescues the phenotype. Intracellular microelectrode studies indicate combined pre-and postsynaptic defects of neuromuscular transmission with evidence for somatic mosaicism in patient 2. Structural studies reveal hypoplastic endplates, fiber-type disproportion, tubular aggregates, and degeneration of muscle fiber organelles resulting in autophagocytosis.Conclusions: DPAGT1 myasthenia affects multiple parameters of neuromuscular transmission, causes fiber-type disproportion and an autophagic myopathy, and can be associated with intellectual disability. We speculate that hypoglycosylation of synapse-specific proteins causes defects in central as well as motor synapses. Neurology ® 2014;82:1822-1830 GLOSSARY AChE 5 acetylcholinesterase; AChR 5 acetylcholine receptor; a-bgt 5 a-bungarotoxin; cDNA 5 complementary DNA; CMS 5 congenital myasthenic syndrome; 3,4-DAP 5 3,4-diaminopyridine; DPAGT1 5 UDP-N-acetylglucosamine-dolichylphosphate N-acetylglucosaminephosphotransferase 1; EP 5 endplate; MEPC 5 miniature endplate current; MEPP 5 miniature endplate potential; STIM1 5 stromal interaction molecule 1.Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Most CMS are caused by defects in endplate (EP)-specific proteins.1 Recently, however, it became apparent that proteins distributed in many tissues, namely the intermediate filament linker plectin 2 and enzymes subserving glycosylation of nascent peptides such as GFPT1, 3,4 DPAGT1, 5 ALG2, and ALG14, 6 are also CMS targets. GFPT1 is the initial and ratelimiting enzyme in the biosynthesis of N-acetylglucosamine, an essential substrate for O-and N-glycosylation.7 DPAGT1 catalyzes the first step, ALG14 in concert with ALG13 catalyzes the second step, and A...

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A missense mutation in a patient with developmental delay affects the activity and structure of the hexosamine biosynthetic pathway enzyme AGX1

et al. 2020

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O-GlcNAcylation is a post-translational modification catalysed by O-GlcNAc transferase (OGT). Missense mutations in OGT have been associated with developmental disorders, OGT-linked congenital disorder of glycosylation (OGT-CDG), which are characterized by intellectual disability. OGT relies on the hexosamine biosynthetic pathway (HBP) for provision of its UDP-GlcNAc donor. We considered whether mutations in UDP-N-acetylhexosamine pyrophosphorylase (UAP1), which catalyses the final step in the HBP, would phenocopy OGT-CDG mutations. A de novo mutation in UAP1 (NM_001324114:c.G685A:p.A229T) was reported in a patient with intellectual disability. We show that this mutation is pathogenic and decreases the stability and activity of the UAP1 isoform AGX1 in vitro. X-ray crystallography reveals a structural shift proximal to the mutation, leading to a conformational change of the N-terminal domain. These data suggest that the UAP1 A229T missense mutation could be a contributory factor to the patient phenotype.

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Clinical features in a large Iranian family with a limb-girdle congenital myasthenic syndrome due to a mutation in DPAGT1

Cited by 30 publications

References 18 publications

Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation

Clinical utility gene card for: DPAGT1 defective congenital disorder of glycosylation

DPAGT1 myasthenia and myopathy

A missense mutation in a patient with developmental delay affects the activity and structure of the hexosamine biosynthetic pathway enzyme AGX1

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