PMM2-CDG: Phenotype and genotype in four affected family members

Bortot, Barbara; Cosentini, Dora; Faletra, Flavio; Biffi, Stefania; Martino, Eleonora De; Carrozzi, Marco; Severini, Giovanni Maria

doi:10.1016/j.gene.2013.07.083

Cited by 16 publications

(11 citation statements)

References 20 publications

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“…Other features variably reported included hypertelorism in 2 (Edwards et al 2006; Kasapkara et al 2017), but hypotelorism in 2 (Pavone et al 1996); downslanted palpebral fissures in 3 (Clayton et al 1992; Bubel et al 2002), while others had upslanted palpebral fissures (Kjaergaard et al 2001; Brum et al 2008); flat nasal bridge in 5 (Harding et al 1988; Tayebi et al 2002; Thong et al 2009; Al-Maawali et al 2014; Kasapkara et al 2017) but high nasal bridge in 4 (Artigas et al 1998; Antoun et al 1999; Laplace et al 2003). A coarse face has been described in older adults (Bortot et al 2013; Barone et al 2015).…”

Section: Resultsmentioning

confidence: 99%

Recognizable phenotypes in CDG

Ferreira

Altassan

Marques‐da‐Silva

et al. 2018

J of Inher Metab Disea

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Pattern recognition, using a group of characteristic, or discriminating features, is a powerful tool in metabolic diagnostic. A classic example of this approach is used in biochemical analysis of urine organic acid analysis, where the reporting depends more on the correlation of pertinent positive and negative findings, rather than on the absolute values of specific markers. Similar uses of pattern recognition in the field of biochemical genetics include the interpretation of data obtained by metabolomics, like glycomics, where a recognizable pattern or the presence of a specific glycan sub-fraction can lead to the direct diagnosis of certain types of congenital disorders of glycosylation. Another indispensable tool is the use of clinical pattern recognition-or syndromology-relying on careful phenotyping. While genomics might uncover variants not essential in the final clinical expression of disease, and metabolomics could point to a mixture of primary but also secondary changes in biochemical pathways, phenomics describes the clinically relevant manifestations and the full expression of the disease. In the current review we apply phenomics to the field of congenital disorders of glycosylation, focusing on recognizable differentiating findings in glycosylation disorders, characteristic dysmorphic features and malformations in PMM2-CDG, and overlapping patterns among the currently known glycosylation disorders based on their pathophysiological basis.

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Section: Resultsmentioning

confidence: 99%

Recognizable phenotypes in CDG

Ferreira

Altassan

Marques‐da‐Silva

et al. 2018

J of Inher Metab Disea

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“…A thorough biochemical characterization of the purified PMM2 mutants can possibly distinguish between the extreme ends of the phenotype, but the genetic background should be taken into account for the grading diagnosis. Actually, it has been observed that the presence of the variant Phe304Ser in the gene ALG6 can worsen the PMM2-CDG phenotype [47,48]. Phe304Ser_ALG6 was also found in the homozygous state in a severe CDG-I associated with dehydrodolichol diphosphate synthase deficiency [49].…”

Section: Discussionmentioning

confidence: 99%

The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

Citro

Cimmaruta

Monticelli

et al. 2018

IJMS

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Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

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“…AHSA1 is regulated by p53 and though roles in the ovary are not understood, AHSA increases PI3K phosphorylation [83] thus suggesting involvement in ovarian processes of importance. PMM2 mutations result in a glycosylation disorder in humans and endoplasmic reticulum stress has been reported in a zebrafish model of PMM2 deficiency [84,85]. Nalp14 mRNA transcript is located in the oocytes of follicles up until the preovulatory stage [86] and Nalp14 mutation is associated with spermatogenic issues in men [87].…”

Section: Discussionmentioning

confidence: 99%

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

Clark

Keating

2019

Biology of Reproduction

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Ataxia–telangiectasia-mutated (ATM) protein recognizes and repairs DNA double strand breaks through activation of cell cycle checkpoints and DNA repair proteins. Atm gene mutations increase female reproductive cancer risk. Phosphoramide mustard (PM) induces ovarian DNA damage and destroys primordial follicles, and pharmacological ATM inhibition prevents PM-induced follicular depletion. Wild-type (WT) C57BL/6 or Atm+/− mice were dosed once intraperitoneally with sesame oil (95%) or PM (25 mg/kg) in the proestrus phase of the estrous cycle and ovaries harvested 3 days thereafter. Atm+/− mice spent ~25% more time in diestrus phase than WT. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) on ovarian protein was performed and bioinformatically analyzed. Relative to WT, Atm+/− mice had 64 and 243 proteins increased or decreased in abundance, respectively. In WT mice, PM increased 162 and decreased 20 proteins. In Atm+/− mice, 173 and 37 proteins were increased and decreased, respectively, by PM. Exportin-2 (XPO2) was localized to granulosa cells of all follicle stages and was 7.2-fold greater in Atm+/− than WT mice. Cytoplasmic FMR1-interacting protein 1 was 6.8-fold lower in Atm+/− mice and was located in the surface epithelium with apparent translocation to the ovarian medulla post-PM exposure. PM induced γH2AX, but fewer γH2AX-positive foci were identified in Atm+/− ovaries. Similarly, cleaved caspase-3 was lower in the Atm+/− PM-treated, relative to WT mice. These findings support ATM involvement in ovarian DNA repair and suggest that ATM functions to regulate ovarian atresia.

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PMM2-CDG: Phenotype and genotype in four affected family members

Cited by 16 publications

References 20 publications

Recognizable phenotypes in CDG

Recognizable phenotypes in CDG

The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

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