Common Origin and Evolution of Glycosyltransferases Using Dol-P-monosaccharides as Donor Substrate

Oriol, Rafaël; Martínez-Duncker, Iván; Chantret, Isabelle; Mollicone, Rosella; Codogno, Patrice

doi:10.1093/oxfordjournals.molbev.a004208

Cited by 83 publications

(93 citation statements)

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“…The sequence encoded by the exon 10 of ALG9 contains a highly evolutionarily conserved stretch of amino acids that is present in all α2/α6 mannosyltransferases in humans and down to S. cerevisiae and is important for the mannose acceptor site of the enzyme. 17 The skipping of exon 10 in our patients is predicted to result in a truncated ALG9 protein lacking these conserved amino acids as well as three putative transmembrane domains and the ERretention signal located at the C-terminal end of the protein. We conclude that the homozygous variant NM_024740.2: c.1173+2T4A in the ALG9 gene is thus likely to result in a nonfunctional enzyme.…”

Section: Discussionmentioning

confidence: 80%

A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

et al. 2015

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A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T4A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3-and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.

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Section: Discussionmentioning

confidence: 80%

A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

et al. 2015

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“…Irrespective of that, the topology of hALG2 is clearly different from that of glycosyltransferases that catalyze at the inner leaflet of the endoplasmic reticulum the transfer of mannose or glucose residues from dolichol-linked donors onto dolichol-linked oligosaccharides. These glycosyltransferases are highly hydrophobic transmembrane proteins predicted to have 8 -13 transmembrane helices (37).…”

Section: Resultsmentioning

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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“…Reduced hALG8 mRNA Expression in Cells from Patient M. P.-In yeast, the ALG8 gene thought to encode the dolichyl-P-glucose:Glc 1 Man 9 GlcNAc 2 -PP-dolichyl ␣3-glucosyltransferase has been cloned (44), and the complete sequence of the putative human ortholog of this gene (EMBL: BC001133 and AJ224875) is available (45). This information allowed us to create a probe in order to examine hALG8 mRNA in the cells from the patient by Northern blot.…”

Section: Figmentioning

confidence: 99%

“…If any mRNA is translated in patient M. P., it is apparent that only the first ϳ20% of the protein, containing only two potential transmembrane regions, is produced rendering it highly unlikely that these two alleles could give rise to active proteins. The dolichyl-P-monosaccharide requiring mannosyltransferases and glucosyltransferases of the LLO pathway are extremely hydrophobic enzymes comprising 10 -14 transmembrane regions (45). The importance of the transmembrane regions for enzyme function is attested to by the observation that several of the disease causing mutations in CDG I are found in or near the membrane spanning regions that occur along the entire length of the defective glycosyltransferases.…”

Section: Figmentioning

confidence: 99%

“…Second, ALG10p adds an ␣2-linked glucose to the LLO, and this enzyme has been shown to have distinct biochemical properties to those of ALG6p and ALG8p. Third, analysis of the amino acid sequences of the three glucosyltransferases reveals that ALG6p and ALG8p are more closely related to each other (59) than either of them are related to ALG10p (45,60).…”

Section: Figmentioning

confidence: 99%

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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

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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.

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Common Origin and Evolution of Glycosyltransferases Using Dol-P-monosaccharides as Donor Substrate

Cited by 83 publications

References 50 publications

A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

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

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