Congenital disorder of glycosylation (CDG) type Ie. A new patient

García‐Silva, María Teresa; Matthijs, Gert; Schollen, E; Cabrera, José Carlos; Pozo, Jaime Sánchez del; Herreros, M Martí; Simón, Rogelio; Maties, M.; Hernández, Eduardo; Hennet, Thierry; Briones, Paz

doi:10.1023/b:boli.0000042984.42433.d8

Cited by 48 publications

(38 citation statements)

References 7 publications

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“…In addition to the misfolded hypoglycosylated proteins unable to leave the ER, the accumulation of free and truncated LLO might contribute towards ER stress [11]. LLO analysis of DPM1-CDG cells by other authors [27] showed an accumulation of the truncated LLO form. In PMM2-CDG patient-derived fibroblasts, the ER stress observed might be caused by a subphysiological glucose concentration that induces the accumulation of LLO intermediates [28].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Visual abnormalities are described in patients with CDG-Id (MIM 601110), including optic nerve atrophy,5 – 7 coloboma of the iris,5 strabismus, and severe visual impairment with abnormal electroretinography 8 9. In CDG-Ie (MIM 601799) patients cortical blindness, esotropia, nystagmus and optic nerve atrophy have been reported 10 11. Optic nerve atrophy,12 horizontal nystagmus, divergent strabismus, lack of visual fixation and amaurosis have been observed in CDG-If (MIM 609180) 13.…”

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Ophthalmological abnormalities in children with congenital disorders of glycosylation type I

Morava

Wosik

Sykut-Cegielska

et al. 2008

British Journal of Ophthalmology

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Ophthalmic findings are frequent in CDG syndrome involving both the anterior and posterior segment of the eye. The disorder might lead to abnormal development of the lens or the retina, cause diminished vision, alter ocular motility and intraocular pressure. We suggest routine screening and follow-up for ophthalmological anomalies in all children diagnosed with CDG syndrome to provide early treatment and adequate counselling.

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“…The clinical pictures of the five patients identified to date (8) are most frequently characterized by developmental delay and severe neurologic problems, among which seizures and acquired microcephaly are prominent. In cells from the patients, the Dol-P-Man synthase activity is severely diminished.…”

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confidence: 99%

A New Intronic Mutation in the DPM1 Gene Is Associated With a Milder Form of CDG Ie in Two French Siblings

et al. 2006

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Congenital disorders of glycosylation (CDG) type I (CDG I) are rare autosomal recessive diseases caused by deficiencies in the assembly of the dolichol-linked oligosaccharide (DLO) that is required for N-glycoprotein biosynthesis. CDG Ie is due to a defect in the synthesis of dolichyl-phosphoryl-mannose (Dol-P-Man), which is needed for DLO biosynthesis as well as for other glycosylation pathways. Human Dol-P-Man synthase is a heterotrimeric complex composed of DPM1p, DPM2p, and DPM3p, with DPM1p being the catalytic subunit. Here, we report two new CDG Ie patients who present milder symptoms than the five other CDG Ie patients described to date. The clinical pictures of the patients MS and his sister MT are dominated by major ataxia, with no notable hepatic involvement. MS cells accumulate the immature DLO species Dol-PP-GlcNAc 2 Man 5 and possess only residual Dol-P-Man synthase activity. One homozygous intronic mutation, g.IVS4 -5TϾA, was found in the DPM1 gene, leading to exon skipping and transcription of a shortened transcript. Moreover, DPM1 expression was reduced by more than 90% in MS cells, in a nonsense-mediated mRNA decay (NMD)-independent manner. Full analysis of the DPM2 and DPM3 genes revealed a decrease in DPM2 expression and normal expression of DPM3. This description emphasizes the large spectrum of symptoms characterizing CDG I patients. N-glycan biosynthesis starts by the construction of a DLO in the endoplasmic reticulum (ER) membrane. Once completed, the tetradecasaccharide (GlcNAc 2 Man 9 Glc 3 ) of the mature DLO is transferred onto nascent glycoproteins containing the consensus sequence Asn-X-Thr/Ser (where X can be any amino acid except Pro). This oligosaccharide is then trimmed by ER and Golgi-resident glycosidases and glycosyltransferases to permit the proper localization and activity of the N-glycoprotein.The last four mannose residues of the mature DLO are added by enzymes that use Dol-P-Man as a donor substrate. In mammals, Dol-P-Man synthase is composed of three subunits: DPM1p, DPM2p, and DPM3p (2). DPM2p and DPM3p are ER-resident, integral membrane proteins that interact with soluble DPM1p to ensure its correct localization and enzymic activity. Dol-P-Man is an important compound because, besides N-glycosylation, it is a substrate for O-mannosylation, glycophosphatidyl inositol (GPI)-anchor biosynthesis (3) and C-mannosylation (4). CDG I are rare autosomal recessive diseases caused by deficiencies of DLO biosynthetic enzymes. Up to 12 subtypes (CDG Ia to IL) have been described to date, each one involving a different enzymic deficiency in the pathway (5). CDG I patients show a very broad range of clinical and biologic presentations, but severe neurologic symptoms are often predominant. The variation in the symptoms of this newly discovered group of diseases makes genotype to phenotype associations difficult. Therefore, patient descriptions coupled with mutation analyses are required to get more insights into the pathophysiology of the disease. CDG Ie, which was first des...

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Congenital disorder of glycosylation (CDG) type Ie. A new patient

Cited by 48 publications

References 7 publications

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

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

Ophthalmological abnormalities in children with congenital disorders of glycosylation type I

A New Intronic Mutation in the DPM1 Gene Is Associated With a Milder Form of CDG Ie in Two French Siblings

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