Novel Ectodysplasin-A Variants: Structural and Functional Basis of Hypohidrotic Ectodermal Dysplasia DOI Creative Commons
Prashant Ranjan, Chandra Devi,

Rajesh Bansal

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract This study investigates two novel variants in the EDA, c.680G > A (p.G227E) and c.649_666del (Δ215–220), identified X-linked ectodermal dysplasia syndromic tooth agenesis cases. These were through Sanger sequencing mapped to highly conserved regions of EDA. Bioinformatics tools consistently classified them as deleterious, with significant disruptions predicted protein stability, hydrophobicity, secondary structure. Structural analysis revealed that p.G227E caused a glycine-to-glutamic acid substitution, altering hydrophobicity structure, while Δ215–220 disrupted hydrophobic region, leading increased instability Functional studies reduced expression EDA WNT4 proteins, alongside IκB levels decreased NF-κB mRNA expression, indicating impaired EDA-NF-κB signaling. Subcellular localization analyses demonstrated diminished cytoplasmic Variants corroborated by silico predictions. Post-translational modifications (PTMs) gene ontology (GO) alterations processes critical for development, including macromolecule biosynthesis, nitrogen metabolism, receptor Molecular dynamics simulations highlighted rigidity, compact flexibility proteins compared Wild Type (WT). Interestingly, neither variant significantly impacted calcium or mitochondrial potential under normal experimental conditions, suggesting their pathogenic effects arise primarily from interactions signaling pathways. integrates molecular, bioinformatics, functional elucidate pathogenicity these EDA variants, providing insights into mechanisms paving way future therapeutic strategies targeting variants.

Язык: Английский

Novel Ectodysplasin-A Variants: Structural and Functional Basis of Hypohidrotic Ectodermal Dysplasia DOI Creative Commons
Prashant Ranjan, Chandra Devi,

Rajesh Bansal

и другие.

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Abstract This study investigates two novel variants in the EDA, c.680G > A (p.G227E) and c.649_666del (Δ215–220), identified X-linked ectodermal dysplasia syndromic tooth agenesis cases. These were through Sanger sequencing mapped to highly conserved regions of EDA. Bioinformatics tools consistently classified them as deleterious, with significant disruptions predicted protein stability, hydrophobicity, secondary structure. Structural analysis revealed that p.G227E caused a glycine-to-glutamic acid substitution, altering hydrophobicity structure, while Δ215–220 disrupted hydrophobic region, leading increased instability Functional studies reduced expression EDA WNT4 proteins, alongside IκB levels decreased NF-κB mRNA expression, indicating impaired EDA-NF-κB signaling. Subcellular localization analyses demonstrated diminished cytoplasmic Variants corroborated by silico predictions. Post-translational modifications (PTMs) gene ontology (GO) alterations processes critical for development, including macromolecule biosynthesis, nitrogen metabolism, receptor Molecular dynamics simulations highlighted rigidity, compact flexibility proteins compared Wild Type (WT). Interestingly, neither variant significantly impacted calcium or mitochondrial potential under normal experimental conditions, suggesting their pathogenic effects arise primarily from interactions signaling pathways. integrates molecular, bioinformatics, functional elucidate pathogenicity these EDA variants, providing insights into mechanisms paving way future therapeutic strategies targeting variants.

Язык: Английский

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