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

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.

Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis

“…For instance, MD simulations on WT and mutant ND4L-ND6 subunits revealed that the mutations limit the passage of water molecules leading to type 2 diabetes mellitus and cataracts [ 37 ]. Additionally, MD simulations on a mutation in the arylsulfatase A protein altered its structural and functional behavior, ultimately led to metachromatic leukodystrophy [ 38 ]. Identifying the effects of mutations on protein structure is critical for exploring disease pathogenesis at the molecular level.…”