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<p>Mucopolysaccharidoses (MPS) are heterogeneous group of disorders caused by the deficiency of lysosomal enzymatic activities. Deficiencies in these enzymes are required for proper degradation of glycosaminoglycans (GAGs), thus referred as inborn errors of lysosomal GAG metabolism. Arylsulfatase K (ARSK) has been recently characterized as lysosomal hydrolase involved in GAG degradation removing the 2-O-sulfate group from 2-sulfoglucuronate and has been associated with MPS X. A 12-year-old female presented with developmental delay, progressive musculoskeletal abnormalities, and skeletal dysplasia, with symptom onset at 2–3 years of age. Whole exome sequencing [WES], followed by bi-directional Sanger sequencing was performed to identify the culprit gene. As the three-dimensional structure of ARSK has not yet been experimentally resolved, an in silico predicted ARSK model was used for structural modeling, molecular dynamics simulations, and stability analyses to investigate the effect of the identified variant on protein structure and function. Biochemical and molecular analysis revealed likely pathogenic novel variant (c.238T &gt; G; p.Cys80Gly) in the <i>ARSK</i> gene [NM_198150.3]. The identified sequence variant was screened in 2000 in-house exomes from the same ethnic population. Here, we report a novel variant in <i>ARSK</i> gene associated with MPS X, which will help in proper genetic counselling of the family.</p>

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Structural dynamics and stability analysis of a novel ARSK variant confirms its role in MPS type X pathogenesis

  • 期刊论文

  • 发表日期：

    2026年7月28日

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  • Muhammad Bilal,
  • Muhammad Fakhar,
  • Thamir Eid,
  • Nawal Helmi,
  • Misbahuddin Rafeeq,
  • Mehreen Gul,
  • Hammal Khan,
  • Muhammad Umair

摘要

Mucopolysaccharidoses (MPS) are heterogeneous group of disorders caused by the deficiency of lysosomal enzymatic activities. Deficiencies in these enzymes are required for proper degradation of glycosaminoglycans (GAGs), thus referred as inborn errors of lysosomal GAG metabolism. Arylsulfatase K (ARSK) has been recently characterized as lysosomal hydrolase involved in GAG degradation removing the 2-O-sulfate group from 2-sulfoglucuronate and has been associated with MPS X. A 12-year-old female presented with developmental delay, progressive musculoskeletal abnormalities, and skeletal dysplasia, with symptom onset at 2–3 years of age. Whole exome sequencing [WES], followed by bi-directional Sanger sequencing was performed to identify the culprit gene. As the three-dimensional structure of ARSK has not yet been experimentally resolved, an in silico predicted ARSK model was used for structural modeling, molecular dynamics simulations, and stability analyses to investigate the effect of the identified variant on protein structure and function. Biochemical and molecular analysis revealed likely pathogenic novel variant (c.238T > G; p.Cys80Gly) in the ARSK gene [NM_198150.3]. The identified sequence variant was screened in 2000 in-house exomes from the same ethnic population. Here, we report a novel variant in ARSK gene associated with MPS X, which will help in proper genetic counselling of the family.