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Novel In-Frame Duplication Variant Characterization in Late Infantile Metachromatic Leukodystrophy Using Whole-Exome Sequencing and Molecular Dynamics Simulation Publisher Pubmed



Ataei Z1, 2 ; Nouri Z1, 2 ; Tavakoli F3 ; Pourreza MR4 ; Narrei S1, 5 ; Tabatabaiefar MA1, 2
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
  4. 4. Core Research Facilities, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5. Department of Research and Development, ERYTHROGEN Medical Genetics Lab, Isfahan, Iran

Source: PLoS ONE Published:2023


Abstract

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disease caused by a deficiency in the arylsulfatase A (ARSA). ARSA deficiency leads to sulfatide accumulation, which involves progressive demyelination. The profound impact of early diagnosis on MLD treatment options necessitates the development of new or updated analysis tools and approaches. In this study, to identify the genetic etiology in a proband from a consanguineous family with MLD presentation and low ARSA activity, we employed Whole-Exome Sequencing (WES) followed by co-segregation analysis using Sanger sequencing. Also, MD simulation was utilized to study how the variant alters the structural behavior and function of the ARSA protein. GROMACS was applied and the data was analyzed by RMSD, RMSF, Rg, SASA, HB, atomic distance, PCA, and FEL. Variant interpretation was done based on the American College of Medical Genetics and Genomics (ACMG) guidelines. WES results showed a novel homozygous insertion mutation, c.109_126dup (p. Asp37_Gly42dup), in the ARSA gene. This variant is located in the first exon of ARSA, fulfilling the criteria of being categorized as likely pathogenic, according to the ACMG guidelines and it was also found to be co-segregating in the family. The MD simulation analysis revealed this mutation influenced the structure and the stabilization of ARSA and led to the protein function impairment. Here, we report a useful application of WES and MD to identify the causes of a neurometabolic disorder. © 2023 Ataei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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