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<p>Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that can caused by mutations in the EDAR gene, which encodes the Ectodysplasin A receptor, leading to defective ectodermal structure development. This study investigates the molecular impact of a novel homozygous c.730 + 1G &gt; T splice site variant in the EDAR gene, identified in a consanguineous Iranian family with HED. The 10-year-old proband presented with a classic, severe HED phenotype, including anhidrosis (impaired sweating) leading to recurrent hyperthermia, sparse hair, dry skin, and severe oligodontia with only three teeth present. Co-occurring thyroid dysfunction was also noted. To elucidate the variant’s predicted structural and functional consequences (likely exon 8 skipping), Molecular Dynamics (MD) simulations were performed over 50 ns, focusing on the EDAR protein’s conformational dynamics. The simulations revealed that the predicted variant-induced structural alteration leads to a more compact and rigid EDAR structure, significantly reducing its conformational flexibility. This structural change likely disrupts critical receptor interactions and downstream signaling, which are key factors in HED pathogenesis. These findings highlight the power of combining detailed clinical phenotyping with MD simulations in uncovering the precise molecular mechanisms underlying EDAR dysfunction in HED, expanding the mutational spectrum of the gene and supporting precise genetic diagnosis for improved clinical management.</p>

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A case study of a novel homozygous EDAR splice site variant in hypohidrotic ectodermal dysplasia with tooth agenesis: molecular dynamics insights

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Parham Nejati,
  • Teymoor Khosravi,
  • Saba Lorestani,
  • Morteza Oladnabi

摘要

Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that can caused by mutations in the EDAR gene, which encodes the Ectodysplasin A receptor, leading to defective ectodermal structure development. This study investigates the molecular impact of a novel homozygous c.730 + 1G > T splice site variant in the EDAR gene, identified in a consanguineous Iranian family with HED. The 10-year-old proband presented with a classic, severe HED phenotype, including anhidrosis (impaired sweating) leading to recurrent hyperthermia, sparse hair, dry skin, and severe oligodontia with only three teeth present. Co-occurring thyroid dysfunction was also noted. To elucidate the variant’s predicted structural and functional consequences (likely exon 8 skipping), Molecular Dynamics (MD) simulations were performed over 50 ns, focusing on the EDAR protein’s conformational dynamics. The simulations revealed that the predicted variant-induced structural alteration leads to a more compact and rigid EDAR structure, significantly reducing its conformational flexibility. This structural change likely disrupts critical receptor interactions and downstream signaling, which are key factors in HED pathogenesis. These findings highlight the power of combining detailed clinical phenotyping with MD simulations in uncovering the precise molecular mechanisms underlying EDAR dysfunction in HED, expanding the mutational spectrum of the gene and supporting precise genetic diagnosis for improved clinical management.