Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia)

Schollen, E; Kjærgaard, Susanne; Legius, Eric; Schwartz, Marianne; Matthijs, Gert

doi:10.1038/sj.ejhg.5200470

Cited by 102 publications

(85 citation statements)

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“…This is consistent with the situation in CDG-Ia patients, who often show a compound heterozygosity for two mutations, at least one of which has a residual activity. The most common mutation described in CDG-Ia patients, R141H, has never been identified in the homozygous state (19,25). Analysis of the recombinant PMM2 protein with the R141H mutation revealed no rest activity of the mutated protein (11,22).…”

Section: Discussionmentioning

confidence: 96%

Targeted Disruption of the Mouse Phosphomannomutase 2 Gene Causes Early Embryonic Lethality

Thiel

Lübke

Matthijs

et al. 2006

Molecular and Cellular Biology

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Mutations in the cytosolic enzyme phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the Pmm2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the Pmm2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that Pmm2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female Pmm2-null allele is impaired.The attachment of oligosaccharide moieties onto newly synthesized proteins presents one of the most widespread forms of co-and posttranslational modifications that are found in animals, plants, and bacteria. Glycoproteins are most abundant in extracellular fluids and matrices but are also found in subcellular organelles and in cellular membranes. The oligosaccharide moieties of glycoproteins affect their folding, their transport, and their biological activity and stability. The complex process of protein glycosylation requires more than a hundred glycosyltransferases, glycosidases, and transport proteins. Oligosaccharide moieties are connected to glycoproteins predominantly by either N-glycosidic linkages, in which glycans are linked to amino groups of asparagine side chains, or by Oglycosidic linkage, where the glycans are bound to hydroxyl groups of serine or threonine side chains (4).Inborn errors in protein glycosylation in man lead to congenital disorders of glycosylation (CDG), a rapidly growing group of (thus far) 18 monogenic inherited diseases that present most often with a severe neurological phenotype (9,16,17,29). CDG-Ia (OMIM 212065) represents by far the most widespread form of these diseases, affecting about 500 diagnosed patients worldwide. The multisystemic disease presents with hypotonia, psychomotor retardation, peripheral neuropathy, and cerebellar atrophy (8). CDG-Ia is caused by mutations in the gene encoding PMM2 (18, 28), the enzyme which catalyzes in the cytosol the conversion of mannose-6-phosphate to mannose-1-phosphate. Mannose-1-phosphate is further converted to GDP-mannose, the donor substrate for the addition of mannose residues in the biosynthesis of dolichollinked oligosaccharides in N glycosylation. The reduced activity of PMM2 in CDG-Ia patients leads to a decreased amount of GDP-mannose and dolichol-phosphate-mannose, which ends up in shortened lipid-linked oligosaccharides, leading to a reduced transfer of these oligosaccharides to nascent glycoproteins by the oligosaccharyl transferase complex (12). Although the glycosylation deficiency can efficiently be corrected in cultured skin fibroblasts from...

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Section: Discussionmentioning

confidence: 96%

Targeted Disruption of the Mouse Phosphomannomutase 2 Gene Causes Early Embryonic Lethality

Thiel

Lübke

Matthijs

et al. 2006

Molecular and Cellular Biology

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“…R141H and F119L are the most common. R141H is found in more than 75% of Caucasian patients (23). Homozygosity for R141H is incompatible with life; however, patients homozygous for F119L have been found (23).…”

Section: Discussionmentioning

confidence: 99%

Phosphomannose Isomerase Inhibitors Improve N-Glycosylation in Selected Phosphomannomutase-deficient Fibroblasts

Sharma

Ichikawa

et al. 2011

Journal of Biological Chemistry

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“…The second most frequent mutation in both populations was p.D65Y, accounting for 10% (12/118) of the disease alleles; but among the Spanish group of patients, the second most frequent was p.T237M that was found in 10.4% (9/86) of the disease alleles. Discussion PMM2-CDG is an autosomal recessive inherited disorder with an estimated incidence of 1:20,000 Schollen et al 2000). Due to the broad spectrum of clinical signs, including the very mild phenotypes recently described (Perez-Duenas et al 2009;Grunewald 2009), the disease is probably still underdiagnosed.…”

Section: Resultsmentioning

confidence: 99%

The Molecular Landscape of Phosphomannose Mutase Deficiency in Iberian Peninsula: Identification of 15 Population-Specific Mutations

et al. 2011

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PMM2-CDG is an autosomal recessive disorder and the most frequent form of congenital disorder of Nglycosylation, with more than 100 mutations identified to date. Sixty-six patients from 58 unrelated families were diagnosed as PMM2-CDG (CDG-Ia) based on clinical signs or because of a previous affected sibling. They all presented a type 1 serum transferrin isoform pattern, and, in most cases, the disease was confirmed by determining PMM2 activity in fibroblasts and/or lymphocytes. Residual PMM2 activity in fibroblasts ranged from not detectable to 60% of the mean controls. DNA and RNA were isolated from fresh blood or fibroblasts from patients to perform molecular studies of the PMM2 gene, resulting in the identification of 30 different mutations, four of them newly reported here

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Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia)

Cited by 102 publications

References 13 publications

Targeted Disruption of the Mouse Phosphomannomutase 2 Gene Causes Early Embryonic Lethality

Targeted Disruption of the Mouse Phosphomannomutase 2 Gene Causes Early Embryonic Lethality

Phosphomannose Isomerase Inhibitors Improve N-Glycosylation in Selected Phosphomannomutase-deficient Fibroblasts

The Molecular Landscape of Phosphomannose Mutase Deficiency in Iberian Peninsula: Identification of 15 Population-Specific Mutations

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