A comprehensive update of genotype-phenotype correlations in PMM2-CDG: insights from molecular and structural
Tiago Oliveira1, Ricardo Ferraz2,3,4, Luísa Azevedo5,6
1LAQV/REQUIMTE, BioSIM, Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto, Portugal.
Abstract:
PMM2-CDG (phosphomannomutase 2-deficiency) is the most prevalent N-glycosylation disorder and results from impairments of PMM2 activity. This disease presents a large variety of pathogenic variants, which cause a wide phenotypical spectrum. This diversity, together with the low number of affected patients, raises the challenge of determining genotype-phenotype correlations in PMM2-CDG. This type of correlation could be highly significant in determining disease progression, prognosis, severity and in developing genome-personalized therapies. Structural analyses offer a valuable approach for assessing the pathogenic mechanisms within the PMM2 protein structure at a molecular level. Such an approach can reveal novel insights into the consequences of missense variants and their relationship with patients'phenotype. In this comprehensive review, we evaluate at a structural level 41 missense mutations in PMM2-CDG, examining their phenotypical characteristics and clinical severity, protein properties and interference at the enzymatic level. This work broadens the understanding of the intricate relationships between genotype and clinical manifestations of PMM2-CDG.
Insights
Phosphomannomutase 2-deficiency (PMM2-CDG), the most common N-glycosylation disorder, presents diverse genotypes and phenotypes. Structural analysis of 41 missense mutations reveals genotype-phenotype correlations, aiding disease understanding and personalized therapies.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- PMM2-CDG is the most prevalent N-glycosylation disorder, caused by PMM2 enzyme activity impairment.
- The disease exhibits a wide spectrum of phenotypes due to numerous pathogenic variants, complicating genotype-phenotype correlation.
- Understanding these correlations is crucial for predicting disease progression, severity, and developing personalized treatments.
Purpose of the Study:
- To conduct a comprehensive structural analysis of 41 missense mutations in PMM2-CDG.
- To investigate the molecular mechanisms underlying PMM2 missense variants.
- To establish genotype-phenotype correlations by linking structural changes to clinical manifestations.
Main Methods:
- Review and structural analysis of 41 PMM2 missense mutations.
- Evaluation of mutation impact on PMM2 protein structure and enzymatic activity.
- Correlation of structural findings with patient phenotypical characteristics and clinical severity.
Main Results:
- Detailed structural insights into the pathogenic mechanisms of 41 PMM2 missense mutations.
- Identification of how specific variants affect protein properties and enzymatic function.
- Demonstration of relationships between structural alterations, protein dysfunction, and observed clinical phenotypes.
Conclusions:
- Structural analysis provides a valuable approach to understanding PMM2-CDG molecular pathology.
- This study enhances comprehension of genotype-phenotype relationships in PMM2-CDG.
- Findings support the development of genotype-guided, personalized therapeutic strategies for PMM2-CDG patients.
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