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

Jaeken, Jaak; Lefeber, Dirk; Matthijs, Gert

doi:10.1038/ejhg.2015.177

Cited by 11 publications

(19 citation statements)

References 18 publications

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“…1). The full-blown phenotype of this CDG type is very severe, showing early-onset epileptic encephalopathy (EOEE), pronounced muscular hypotonia, severely delayed development, and early death (Jaeken et al 2015). In our cohort this was confirmed as 30% of the cases died before the age of one, and only three lived to be teenagers.…”

Section: Discussionsupporting

confidence: 63%

“…A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype. However, findings otherwise common in CDG, such as night blindness, inverted nipples, and lipodystrophy, have only rarely been reported (Jaeken et al 2015).…”

Section: Introductionmentioning

confidence: 98%

“…Dolichyl-phosphate GlcNAc phosphotransferase 1 (DPAGT1) catalyzes the first step in the biosynthetic pathway of the precursor oligosaccharide for N-linked glycosylation: the transfer of GlcNAc-1-P from UDP-GlcNAc to dolichol phosphate, resulting in the formation of dolichol pyrophosphate GlcNAc (Wu et al 2003). The first patient identified with mutations in DPAGT1 was described in 2003 (Wu et al 2003), and thereafter over 40 patients have been described in publications (Jaeken et al 2015). Interestingly, a recently released manuscript on the preprint server for biology "bioRxiv" investigates in great detail known mutations in DPAGT1, using crystal structures of the enzyme together with either the substrate UDP-GlcNAc or the inhibitor tunicamycin (https://doi.org/ 10.1101/291278).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, a recently released manuscript on the preprint server for biology "bioRxiv" investigates in great detail known mutations in DPAGT1, using crystal structures of the enzyme together with either the substrate UDP-GlcNAc or the inhibitor tunicamycin (https://doi.org/ 10.1101/291278). Two clinically distinguishable phenotypes are seen with the first being a systemic disease with encephalopathy [DPAGT1-CDG (formerly CDG-Ij)] and the second a congenital myasthenic syndrome (DPAGT1-CMS) with tubular aggregates seen in muscle biopsies (Jaeken et al 2015). The DPAGT1-CDG phenotype is most often a severe disease, where more than 80% of the reported patients died before 5 years of age.…”

Section: Introductionmentioning

confidence: 99%

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DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Underhill

Palm

et al. 2018

JIMD Reports

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Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

Underhill

Palm

et al. 2018

JIMD Reports

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“…The former is a severe, multisystem disease, with most patients presenting moderate to severe psychomotor disability, microcephaly, hypotonia and epilepsy. The clinical manifestations of CMS, in contrast, include muscle weakness plus minimal or absent craniobulbar symptoms [ 1 , 2 ]. The primary pathogenic mechanism arising through DPAGT1 mutations that leads to CMS is the hypoglycosylation of acetylcholine receptors in neuron endplates.…”

Section: Introductionmentioning

confidence: 99%

DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress

et al. 2017

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Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates. UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway. The aim of the present study was to examine the effect of six variants in DPAGT1 detected in patients with DPAGT1-CDG, and the role of endoplasmic reticulum stress, as part of the search for therapeutic strategies to use against DPAGT1-CDG. The effect of the six mutations, i.e., c.358C>A (p.Leu120Met), c.791T>G (p.Val264Gly), c.901C>T (p.Arg301Cys), c.902G>A (p.Arg301His), c.1154T>G (p.Leu385Arg), and of the novel mutation c.329T>C (p.Phe110Ser), were examined via the analysis of DPAGT1 transcriptional profiles and GTP levels in patient-derived fibroblasts. In addition, the transient expression of different mutations was analysed in COS-7 cells. The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane. The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG. Even so, the fibroblasts of patients with DPAGT1-CDG seemed to be more sensitive to the stressor tunicamycin. The present work improves our knowledge of DPAGT1-CDG and provides bases for developing tailored splicing and folding therapies.

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DPAGT1‐CDG: Recurrent fetal death

Tao

Sun

Zhai

et al. 2023

Birth Defects Research

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BackgroundCongenital disorders of glycosylation (CDG) are a series of relatively uncommon genetic disorders, and variants in the dolichyl‐phosphate N‐acetylglucosamine‐1‐phosphotransferase (DPAGT1) gene can cause DPAGT1‐CDG, which is characterized by multisystem abnormalities: failure to thrive, psychomotor retardation, seizures, etc.PatientsTwo fetuses in a nonconsanguineous family recurrently presented with irregular skull morphology, micrognathia, adduction and supination by prenatal ultrasound. They were finally found dead in utero. Pedigree whole exome sequencing revealed novel compound heterozygous variants in the DPAGT1 gene. We also reviewed 11 previous reports associated with DPAGT1‐CDG.ConclusionsWe report novel variants in the DPAGT1 gene in two fetuses from the same family with intrauterine death.

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

Cited by 11 publications

References 18 publications

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients

DPAGT1-CDG: Functional analysis of disease-causing pathogenic mutations and role of endoplasmic reticulum stress

DPAGT1‐CDG: Recurrent fetal death

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