Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie)

Kim, Soohyun; Westphal, Vibeke; Srikrishna, Geetha; Mehta, Darshini P.; Peterson, Sandra M.; Filiano, James J.; Karnes, Pamela S.; Patterson, Marc C.; Freeze, Hudson H.

doi:10.1172/jci7302

Cited by 164 publications

(140 citation statements)

References 37 publications

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“…For instance, one CDG-Ic patient lacked heparan sulfate proteoglycan on small intestine enterocytes and developed protein-losing enteropathy only during viral-induced gastroenteritis. 20 The amount and distribution of heparan sulfate improved in the small intestine after recovery, but it was always normal in the more slowly turning over cells in the stomach, esophagus, and colon. Localized proliferation in response to infection seemed to tax the already compromised glycosylation apparatus, leading to enteral protein loss.…”

Section: Discussionmentioning

confidence: 96%

“…Localized proliferation in response to infection seemed to tax the already compromised glycosylation apparatus, leading to enteral protein loss. 20 Other stresses, such as maternal fever during critical gestational periods could affect thermolabile glycosylation phenotypes. Inadequate maternal or fetal nutrition could contribute additional environmental stress.…”

Section: Discussionmentioning

confidence: 99%

“…20 Enzyme assays PMI (EC 5.3.1.8) and PMM (EC 5.4.28) assays were carried out as described previously. 20 -23 …”

Section: Analysis Of Serum Transferrinmentioning

confidence: 99%

“…20,24 Sequence analysis of the cDNA and genomic DNA Extractions of total RNA and DNA, first-strand PCR, amplification, purification, and sequencing analysis of the PMM2 gene were done as described previously. 25 …”

Section: Radioactive Labelingmentioning

confidence: 99%

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Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Westphal

Peterson

Patterson

et al. 2001

Genetics in Medicine

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Purpose: Congenital disorders of glycosylation (CDG) result from mutations in N-glycan biosynthesis. Mutations in phosphomannomutase (PMM2) cause CDG-Ia. Here, we report four clinically mild patients and their mutations in PMM2. Methods: Analysis of the PMM2 cDNA and gene revealed the mutations affecting the glycosylation efficiency. Results: The patients have 30% to 50% normal PMM activity in fibroblasts due to different mutations in PMM2, and we studied the effect of each mutation on the PMM activity in a Saccharomyces cerevisiae expression system. Conclusions: Each patient carried a severe mutation that decreased the PMM activity to less than 10% as well as a relatively mild mutation. A new mutation, deletion of base 24, changed the reading frame. The C9Y, C241S, and L32R mutations showed 27% to 45% activity when expressed in the eukaryotic expression system, and the more severe D148N was shown to be thermolabile. Genet Med 2001:3(6):393-398.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

“…20 Enzyme assays PMI (EC 5.3.1.8) and PMM (EC 5.4.28) assays were carried out as described previously. 20 -23 …”

Section: Analysis Of Serum Transferrinmentioning

confidence: 99%

Section: Radioactive Labelingmentioning

confidence: 99%

See 2 more Smart Citations

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Westphal

Peterson

Patterson

et al. 2001

Genetics in Medicine

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“…Decreased availability of the substrate Dol-P-Man, such as caused by mutations in the Dol-P-Man synthase subunit genes DPM1 (OMIM ID: 603503) [26,27] and DPM3 (OMIM ID: 605951) [28] (Fig. 1, 2), lead to the accumulation of the incomplete LLO and thereby to incomplete N-glycosylation site occupancy on newly synthesized glycoproteins.…”

Section: Defects Of Lipid-linked Oligosaccharide Biosynthesismentioning

confidence: 99%

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

116

103

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib)

et al. 2000

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CDG‐Ib is the “gastro‐intestinal” type of the congenital disorders of glycosylation (CDG) and a potentially treatable disorder. It has been described in patients presenting with congenital hepatic fibrosis and protein losing enteropathy. The symptoms result from hypoglycosylation of serum‐ and other glycoproteins. CDG‐Ib is caused by a deficiency of mannose‐6‐phosphate isomerase (synonym: phosphomannose isomerase, EC 5.3.1.8), due to mutations in the MPI gene. We determined the genomic structure of the MPI gene in order to simplify mutation detection. The gene is composed of 8 exons and spans only 5 kb. Eight (7 novel) different mutations were found in seven patients with a confirmed phosphomannose isomerase deficiency, analyzed in the context of this study: six missense mutations, a splice mutation and one insertion. In the last, the mutation resulted in an unstable transcript, and was hardly detectable at the mRNA level. This emphasizes the importance of mutation analysis at the genomic DNA level. Hum Mutat 16:247–252, 2000. © 2000 Wiley‐Liss, Inc.

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Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie)

Cited by 164 publications

References 37 publications

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib)

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