A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If)

Kranz, Christian; Denecke, Jonas; Lehrman, Mark A.; Ray, Sutapa; Kienz, Petra; Kreissel, Gunilla; Sagi, Dijana; Peter‐Katalinić, Jasna; Freeze, Hudson H.; Schmid, Thomas E.; Jackowski-Dohrmann, Sabine; Harms, Erik; Marquardt, Thorsten

doi:10.1172/jci13635

Cited by 113 publications

(82 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microheterogeneity of serum glycoproteins has been studied by proteomics in patients with chronic alcohol abuse and compared with patients with carbohydrate-deficient glycoprotein syndrome [32,88]. In alcoholism, abnormal isoforms of transferrin and a1-antitrypsin were devoid of a variable number of entire N-glycan moieties and were identical to those present in carbohydrate-deficient glycoprotein syndrome type 1.…”

Section: Genetic Diseasesmentioning

confidence: 99%

Recent advances in blood‐related proteomics

et al. 2005

View full text Add to dashboard Cite

Service régional vaudois de transfusion sanguine, Lausanne, SwitzerlandBlood is divided in two compartments, namely, plasma and cells. The latter contain red blood cells, leukocytes, and platelets. From a descriptive medical discipline, hematology has evolved towards a pioneering discipline where molecular biology has permitted the development of prognostic and diagnostic indicators for disease. The recent advance in MS and protein separation now allows similar progress in the analysis of proteins. Proteomics offers great promise for the study of proteins in plasma/serum, indeed a number of proteomics databases for plasma/ serum have been established. This is a very complex body fluid containing lipids, carbohydrates, amino acids, vitamins, nucleic acids, hormones, and proteins. About 1500 different proteins have recently been identified, and a number of potential new markers of diseases have been characterized. Here, examples of the enormous promise of plasma/serum proteomic analysis for diagnostic/prognostic markers and information on disease mechanism are given. Within the blood are also a large number of different blood cell types that potentially hold similar information. Proteomics of red blood cells, until now, has not improved our knowledge of these cells, in contrast to the major progresses achieved while studying platelets and leukocytes. In the future, proteomics will change several aspects of hematology.

show abstract

Section: Genetic Diseasesmentioning

confidence: 99%

Recent advances in blood‐related proteomics

et al. 2005

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

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

View full text Add to dashboard Cite

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...

show abstract

“…Theoretically, mutations in any of the genes encoding for the 30 or so proteins involved in this biosynthetic pathway could lead to glycoprotein hypoglycosylation in CDG I patients. However, mutations in only 7 of the genes encoding proteins of the glycosylation pathway have so far been shown to underlie CDG I, and these 7 cases have been classified as CDG I subtypes a-g (Ia, phosphomannomutase 2 (7,8); Ib, phosphomannose isomerase (9, 10); Ic, dolichyl-P-Glc:Man 9 GlcNAc 2 -PP-dolichyl ␣3-glucosyltransferase (11-13); Id, dolichyl-P-Man:Man 5 GlcNAc 2 -PP-dolichyl ␣3-mannosyltransferase (14); Ie, dolichol-P-Man synthase I (15,16); If, the MPDU1 gene product known to facilitate dolichyl-P-Glc and dolichyl-P-Man utilization (17,18); and Ig, dolichyl-P-Man: Man 7 GlcNAc 2 -PP-dolichyl ␣6-mannosyltransferase (19 -21)). Although there are too few patients representing each subtype of the disease to draw precise genotype/phenotype relationships, CDG Ib (PMI deficiency) generally presents as a disease in which central nervous system defects are absent (9,10).…”

mentioning

confidence: 99%

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

Chantret¹,

Dancourt²,

Dupré³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The underlying causes of type I congenital disorders of glycosylation (CDG I) have been shown to be mutations in genes encoding proteins involved in the biosynthesis of the dolichyl-linked oligosaccharide (Glc 3 Man 9 GlcNAc 2 -PP-dolichyl) that is required for protein glycosylation. Here we describe a CDG I patient displaying gastrointestinal problems but no central nervous system deficits. Fibroblasts from this patient accumulate mainly Man 9 GlcNAc 2 -PP-dolichyl, but in the presence of castanospermine, an endoplasmic reticulum glucosidase inhibitor Glc 1 Man 9 GlcNAc 2 -PP-dolichyl predominates, suggesting inefficient addition of the second glucose residue onto lipid-linked oligosaccharide. Northern blot analysis revealed the cells from the patient to possess only 10 -20% normal amounts of mRNA encoding the enzyme, dolichyl-P-glucose:Glc 1 Man 9 GlcNAc 2 -PP-dolichyl ␣3-glucosyltransferase (hALG8p), which catalyzes this reaction. Sequencing of hALG8 genomic DNA revealed exon 4 to contain a base deletion in one allele and a base insertion in the other. Both mutations give rise to premature stop codons predicted to generate severely truncated proteins, but because the translation inhibitor emetine was shown to stabilize the hALG8 mRNA from the patient to normal levels, it is likely that both transcripts undergo nonsensemediated mRNA decay. As the cells from the patient were successfully complemented with wild type hALG8 cDNA, we conclude that these mutations are the underlying cause of this new CDG I subtype that we propose be called CDG Ih.

show abstract

A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If)

Cited by 113 publications

References 12 publications

Recent advances in blood‐related proteomics

Recent advances in blood‐related proteomics

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

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

Contact Info

Product

Resources

About