A Deficiency in Dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl α3-Glucosyltransferase Defines a New Subtype of Congenital Disorders of Glycosylation

Chantret, Isabelle; Dancourt, Julia; Dupré, Thierry; Delenda, Christophe; Bucher, Stéphanie; Vuillaumier‐Barrot, Sandrine; Baulny, Hélène Ogier de; Peletan, Céline; Danos, Olivier; Seta, Nathalie; Durand, Geneviève; Oriol, Rafaël; Codogno, Patrice; Moore, Stuart

doi:10.1074/jbc.m211950200

Cited by 81 publications

(77 citation statements)

References 62 publications

(49 reference statements)

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“…Severe CNS involvement is observed in practically all CDG patients, except CDG-Ib (ϳ20 known patients) (1-3) ranging from mild developmental impairment to severe brain malformations and significant motor and cognitive dysfunction. One patient with CDG-Ih also had mainly hepato-intestinal problems (8), but others had severe developmental delay and multi-organ failure (9). Here we describe four children affected by novel forms of CDG-X presenting as isolated cryptogenic chronic liver disease, coagulopathy, and multiple serum protein abnormalities without other symptoms previously seen in known CDG patients.…”

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confidence: 93%

Cryptogenic Liver Disease in Four Children: A Novel Congenital Disorder of Glycosylation

et al. 2006

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ABSTRACT:We investigated the metabolic defect(s) of four children who presented with isolated cryptogenic chronic liver disease, coagulopathy, and abnormalities of several unrelated serum glycoproteins. Analysis of the patients' serum glycoproteins and fibroblasts suggest they have a novel congenital disorder of glycosylation (CDG). All had abnormal transferrin (Tf) isoelectric focusing (IEF) profiles. More detailed analysis of Tf by electrospray ionization mass spectrometry (ESI-MS) showed a plethora of abnormal glycosylations that included loss of 1-2 sialic acids and 1-2 galactose units, typical of Group II defects. Tf from two patients also lacked 1-2 entire oligosaccharide chains, typical of Group One disorders. Total serum N-glycans were analyzed by HPLC and matrix-assisted laser desorption/ionization mass spectrometry and also showed increased proportion of neutral glycan chains lacking sialic acids and galactose units. Analysis of patient fibroblasts eliminated CDG-Ia, through CDG-Ih, -IL and CDG-IId. Our results suggest that a subset of children with clinically asymptomatic, cryptogenic hypertransaminasemia and/or liver steato-fibrosis may represent a novel type of CDG-X with an unknown defect(s). Clinicians are encouraged to test such patients for abnormal Tf glycosylation by ESI-MS.

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confidence: 93%

Cryptogenic Liver Disease in Four Children: A Novel Congenital Disorder of Glycosylation

et al. 2006

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“…Skin biopsy fibroblasts (3 ϫ 75 cm 2 tissue culture flasks) were scraped into ice-cold phosphate-buffered saline and pelleted, and microsomal fractions were obtained as described previously (11). Dol-P-Man synthase activity was measured by incubating microsomal 14 C]Man (248 mCi/mmol, Amersham Life Science, Orsay, France) was added to the mixtures, which were then incubated for 20 min at 37°C.…”

Section: Methodsmentioning

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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“…Defects of the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins compose CDG type I, whereas CDG type II includes all defects of trimming and elongation of N-linked oligosaccharides (4). In the past 7 years the molecular nature of eight CDG-I and four CDG-II types could be identified (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

A New Type of Congenital Disorders of Glycosylation (CDG-Ii) Provides New Insights into the Early Steps of Dolichol-linked Oligosaccharide Biosynthesis

Thiel

Schwarz

Peng

et al. 2003

Journal of Biological Chemistry

113

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Deficiency of GDP-Man:Man 1 GlcNAc 2 -PP-dolichol mannosyltransferase (hALG2), is the cause of a new type of congenital disorders of glycosylation (CDG) designated CDG-Ii. The patient presented normal at birth but developed in the 1st year of life a multisystemic disorder with mental retardation, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities. An accumulation of Man 1 GlcNAc 2 -PP-dolichol and Man 2 GlcNAc 2 -PP-dolichol was observed in skin fibroblasts of the patient. Incubation of patient fibroblast extracts with Man 1 GlcNAc 2 -PP-dolichol and GDP-mannose revealed a severely reduced activity of the mannosyltransferase elongating Man 1 GlcNAc 2 -PP dolichol. Because the Saccharomyces cerevisiae mutant alg2-1 was known to accumulate the same shortened dolichol-linked oligosaccharides as the patient, the yeast ALG2 sequence was used to identify the human ortholog. Genetic analysis revealed that the patient was heterozygous for a single nucleotide deletion and a single nucleotide substitution in the human ortholog of yeast ALG2. Expression of wild type but not of mutant hALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in the alg2-1 yeast cells. hALG2 was shown to act as an ␣1,3-mannosyltransferase. The resulting Man␣1,3-ManGlcNAc 2 -PP dolichol is further elongated by a yet unknown ␣1,6-mannosyltransferase.Congenital disorders of glycosylation (CDG) 1 compose a rapidly growing group of inherited multisystemic disorders in man, which are commonly associated with severe psychomotor and mental retardation (1). The characteristic biochemical feature of CDG is defective glycosylation of proteins due to mutations in genes required for the biosynthesis of N-linked oligosaccharides.The attachment of oligosaccharide chains onto newly synthesized proteins is one of the most widespread forms of co-and post-translational modifications and is found in animals, plants, and bacteria. Glycoproteins are located inside cells predominantly in subcellular organelles and in cellular membranes and most abundantly in extracellular fluids and matrices. The oligosaccharide moiety of the glycoproteins can affect their folding, their transport, as well as their biological activity and stability (2, 3). The complex process of protein glycosylation requires more than a hundred glycosyltransferases, glycosidases, and transport proteins. CDG are classified into two groups. Defects of the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins compose CDG type I, whereas CDG type II includes all defects of trimming and elongation of N-linked oligosaccharides (4). In the past 7 years the molecular nature of eight CDG-I and four CDG-II types could be identified (5-24).Here we describe for the first time a molecular defect in glycoprotein biosynthesis in man which affects at the cytosolic side of the endoplasmic reticulum the transfer of mannosyl residues from GDP-Man to Man 1 Glc...

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A Deficiency in Dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl α3-Glucosyltransferase Defines a New Subtype of Congenital Disorders of Glycosylation

Cited by 81 publications

References 62 publications

Cryptogenic Liver Disease in Four Children: A Novel Congenital Disorder of Glycosylation

Cryptogenic Liver Disease in Four Children: A Novel Congenital Disorder of Glycosylation

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

A New Type of Congenital Disorders of Glycosylation (CDG-Ii) Provides New Insights into the Early Steps of Dolichol-linked Oligosaccharide Biosynthesis

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