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Background <p>This study examined a consanguineous family affected by autosomal recessive Sjögren-Larsson syndrome (SLS) that is characterized by congenital ichthyosis, intellectual disabilities, and spastic diplegia. SLS is a rare inborn error of lipid metabolism resulting from mutations in the <i>ALDH3A2</i> gene, leading to a deficiency in the fatty aldehyde dehydrogenase (FALDH) enzyme.</p> Methods and results <p>We employed homozygosity-by-descent (HBD) mapping followed by whole-exome sequencing (WES) for mutation identification and conducted protein structure modeling and enzyme assays to determine the functional consequences of the mutation. HBD mapping and WES in a patient with SLS identified a recurrent missense mutation NM_000382:c.C682T: p.(Arg228Cys) in the 5th exon of the <i>ALDH3A2</i> gene. Protein structural modeling and docking studies indicated significant alterations in the structural and interactional properties of the mutant ALDH3A2. Enzyme analysis of serum extracts revealed reduced ALDH enzyme activity in both affected and carrier individuals.</p> Conclusion <p>This study confirmed the association between diminished ALDH activity and the severity of clinical manifestations, including developmental delay, ichthyosis, spasticity, and cognitive disability. To our knowledge, this is the first report of an <i>ALDH3A2</i> mutation in a Pakistani family. Our findings reinforce evidence that the NM_000382:c.C682T: p.(Arg228Cys) mutation in ALDH3A2 is causative of SLS, underscoring the importance of genetic counseling and early biochemical diagnosis for families at risk of SLS.</p>

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Mutation mapping and functional characterization of a missense mutation p.Arg228Cys in ALDH3A2 gene causing Sjögran-Larson syndrome

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Muhammad Zeeshan Ali,
  • Samia Sattar,
  • Abdulfatah M. Alayoubi,
  • Shakil Abbas,
  • Mohammed Turki Hussain Alharthi,
  • Alwaleed Fahad H. Altemani,
  • Muhammad Latif,
  • Muzammil Ahmad Khan,
  • Christian Windpassinger

摘要

Background

This study examined a consanguineous family affected by autosomal recessive Sjögren-Larsson syndrome (SLS) that is characterized by congenital ichthyosis, intellectual disabilities, and spastic diplegia. SLS is a rare inborn error of lipid metabolism resulting from mutations in the ALDH3A2 gene, leading to a deficiency in the fatty aldehyde dehydrogenase (FALDH) enzyme.

Methods and results

We employed homozygosity-by-descent (HBD) mapping followed by whole-exome sequencing (WES) for mutation identification and conducted protein structure modeling and enzyme assays to determine the functional consequences of the mutation. HBD mapping and WES in a patient with SLS identified a recurrent missense mutation NM_000382:c.C682T: p.(Arg228Cys) in the 5th exon of the ALDH3A2 gene. Protein structural modeling and docking studies indicated significant alterations in the structural and interactional properties of the mutant ALDH3A2. Enzyme analysis of serum extracts revealed reduced ALDH enzyme activity in both affected and carrier individuals.

Conclusion

This study confirmed the association between diminished ALDH activity and the severity of clinical manifestations, including developmental delay, ichthyosis, spasticity, and cognitive disability. To our knowledge, this is the first report of an ALDH3A2 mutation in a Pakistani family. Our findings reinforce evidence that the NM_000382:c.C682T: p.(Arg228Cys) mutation in ALDH3A2 is causative of SLS, underscoring the importance of genetic counseling and early biochemical diagnosis for families at risk of SLS.