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

Westphal, Vibeke; Peterson, Sandra M.; Patterson, Marc C.; Tournay, Anne; Blumenthal, Andrea; Treacy, Eileen P.; Freeze, Hudson H.

doi:10.1097/00125817-200111000-00003

Cited by 47 publications

(32 citation statements)

References 50 publications

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“…In this study we have included some of the missense changes previously expressed (p.L32R, p.D65Y, p.R123Q, p.R141H, p.E197A and p.C241S) (Pirard et al 1999;Kjaergaard et al 1999;Le Bizec et al 2005;Westphal et al 2001), along with the variant changes not studied elsewhere (p.V44A, p.P113L p.T118S, p.F157S, p.P184T, p.F207S, p.D209G and p.T237M).…”

Section: Expression Analysis Of Missense Mutationsmentioning

confidence: 99%

Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2‐CDG)

Vega

Pérez‐Cerdá

Abia

et al. 2011

J of Inher Metab Disea

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Deficiency of phosphomannomutase (PMM2, MIM#601785) is the most common congenital disorder of glycosylation. Herein we report the genetic analysis of 22 Spanish PMM2 deficient patients and the functional analysis of 14 nucleotide changes in a prokaryotic expression system in order to elucidate their molecular pathogenesis. PMM2 activity assay revealed the presence of six protein changes with no enzymatic activities (p.R123Q, p.R141H, p.F157S, p.P184T, p.F207S and p.D209G) and seven mild protein changes with residual activities ranging from 16 to 54% (p.L32R, p.V44A p.D65Y, p.P113L p.T118S, p.T237M and p.C241S) and also one variant change with normal activity (p.E197A). The results obtained from Western blot analysis, degradation time courses of 11 protein changes and structural analysis of the PMM2 protein, suggest that the loss-of-function of most mutant proteins is based on their increased susceptibility to degradation or aggregation compared to the wild type protein, considering PMM2 deficiency as a conformational disease. We have identified exclusively catalytic protein change (p.D209G), catalytic protein changes affecting protein stability (p.R123Q and p.R141H), two protein changes disrupting the dimer interface (p.P113L and p.T118S) and several misfolding changes (p.L32R, p.V44A, p.D65Y, p.F157S, p.P184T, p.F207S, p.T237M and p.C241S). Our current work opens a promising therapeutic option using pharmacological chaperones to revert the effect of the characterized misfolding mutations identified in a wide range of PMM2 deficient patients.

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Section: Expression Analysis Of Missense Mutationsmentioning

confidence: 99%

Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2‐CDG)

Vega

Pérez‐Cerdá

Abia

et al. 2011

J of Inher Metab Disea

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“…Some missense changes have been functionally analyzed to improve our understanding of the molecular mechanisms of the disease. Since the total lack of the PMM2 gene product is lethal, no patient with two copies of any inactivating mutation has ever been recorded [Le Bizec et al, 2005;Pirard et al, 1999;Westphal et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of three splicing mutations identified in the PMM2 gene: Toward a new therapy for congenital disorder of glycosylation type Ia

et al. 2009

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The congenital disorders of glycosylation (CDG) are a group of diseases caused by genetic defects affecting N-glycosylation. The most prevalent form of CDG-type Ia-is caused by defects in the PMM2 gene. This work reports the study of two new nucleotide changes (c.256-1G>C and c.640-9T>G) identified in the PMM2 gene in CDG1a patients, and of a previously described deep intronic nucleotide change in intron 7 (c.640-15479C>T). Cell-based splicing assays strongly suggest that all these are disease-causing splicing mutations. The c.256-1G>C mutation was found to cause the skipping of exons 3 and 4 in fibroblast cell lines and in a minigene expression system. The c.640-9T>G mutation was found responsible for the activation of a cryptic intronic splice-site in fibroblast cell lines and in a hybrid minigene when cotransfected with certain serine/arginine-rich (SR) proteins. Finally, the deep intronic change c.640-15479C>T was found to be responsible for the activation of a pseudoexon sequence in intron 7. The use of morpholino oligonucleotides allowed the production of correctly spliced mRNA that was efficiently translated into functional and immunoreactive PMM protein. The present results suggest a novel mutation-specific approach for the treatment of this genetic disease (for which no effective treatment is yet available), and open up therapeutic possibilities for several genetic disorders in which deep intronic changes are seen.

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“…High residual PMM activity in fibroblasts may be a potential pitfall, as a patient may be considered normal upon analysis. 40,41 Why most CDG patients develop neuronal problems is not fully known. The structures of N-linked glycans of the brain differ a lot from glycans of other organs and there are a multitude of unusual structures found in brain tissue.…”

Section: Figmentioning

confidence: 99%

The congenital disorders of glycosylation: A multifaceted group of syndromes

Eklund

Freeze

2006

NeuroRX

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Summary:The congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic syndromes with a wide symptomatology and severity. They all stem from deficient N-glycosylation of proteins. To date the group contains 18 different subtypes: 12 of Type I (disrupted synthesis of the lipid-linked oligosaccharide precursor) and 6 of Type II (malfunctioning trimming/processing of the protein-bound oligosaccharide). Main features of CDG involve psychomotor retardation; ataxia; seizures; retinopathy; liver fibrosis; coagulopathies; failure to thrive; dysmorphic features, including inverted nipples and subcutaneous fat pads; and strabismus. No treatment currently is available for the vast majority of these syndromes (CDG-Ib and CDG-IIc are exceptions), even though attempts to synthesize drugs for the most common subtype, CDG-Ia, have been made. In this review we will discuss the individual syndromes, with focus on their neuronal involvement, available and possible treatments, and future directions.

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

Cited by 47 publications

References 50 publications

Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2‐CDG)

Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2‐CDG)

Functional analysis of three splicing mutations identified in the PMM2 gene: Toward a new therapy for congenital disorder of glycosylation type Ia

The congenital disorders of glycosylation: A multifaceted group of syndromes

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