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Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation

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 necessi...

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Autores principales: Ataei, Zahra, Nouri, Zahra, Tavakoli, Farial, Pourreza, Mohammad Reza, Narrei, Sina, Tabatabaiefar, Mohammad Amin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970088/
https://www.ncbi.nlm.nih.gov/pubmed/36848337
http://dx.doi.org/10.1371/journal.pone.0282304
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author Ataei, Zahra
Nouri, Zahra
Tavakoli, Farial
Pourreza, Mohammad Reza
Narrei, Sina
Tabatabaiefar, Mohammad Amin
author_facet Ataei, Zahra
Nouri, Zahra
Tavakoli, Farial
Pourreza, Mohammad Reza
Narrei, Sina
Tabatabaiefar, Mohammad Amin
author_sort Ataei, Zahra
collection PubMed
description 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.
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spelling pubmed-99700882023-02-28 Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation Ataei, Zahra Nouri, Zahra Tavakoli, Farial Pourreza, Mohammad Reza Narrei, Sina Tabatabaiefar, Mohammad Amin PLoS One Research Article 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. Public Library of Science 2023-02-27 /pmc/articles/PMC9970088/ /pubmed/36848337 http://dx.doi.org/10.1371/journal.pone.0282304 Text en © 2023 Ataei et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ataei, Zahra
Nouri, Zahra
Tavakoli, Farial
Pourreza, Mohammad Reza
Narrei, Sina
Tabatabaiefar, Mohammad Amin
Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
title Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
title_full Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
title_fullStr Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
title_full_unstemmed Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
title_short Novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
title_sort novel in-frame duplication variant characterization in late infantile metachromatic leukodystrophy using whole-exome sequencing and molecular dynamics simulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970088/
https://www.ncbi.nlm.nih.gov/pubmed/36848337
http://dx.doi.org/10.1371/journal.pone.0282304
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