Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism

BackgroundThe most common type of metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by recessive mutations in ARSA. The biological process of MLD disease caused by candidate pathogenic mutations in the ARSA gene remains unclear.\n\nMethodsWe used whole-exome sequencing (WES) and Sanger sequencing to identify the pathogenic mutation in a Chinese family. Literature review and protein three-dimensional structure prediction were performed to analyse the potential pathogenesis of the identified mutations. Overexpression cell models of wild-type and mutated ARSA genes were constructed to obtain expression profiles, and weighted gene co-expression network analysis (WGCNA), hub gene detection and protein-protein interaction (PPI) analysis were carried out to compare the biological changes caused by candidate pathogenic mutations.\n\nResultsWe identified an ARSA c.925G>A homozygous mutation from a Chinese late-infantile MLD patient, the first report of this mutation in Asia. According to the literature and protein structure analysis, three mutations of c.925G (c.925G>A, c.925G>T, c.925G>C) in the ARSA gene were pathogenic. The transcriptome of four ARSA overexpression cell models (c.925G, c.925G>A, c.925G>T, c.925G>C) were analysed by WGCNA, Hub genes and PPI complexes.RNA-seq and bioinformatics results indicate that the mutations at c.925G cause comprehensive molecular changes related to energy metabolism, ion binding, vesicle transport and transport.\n\nConclusionWe identified a pathogenic mutation, ARSA homozygosity c.925G>A, from a Chinese MLD family. All three mutations of c.925G in the ARSA gene are pathogenic and may cause disease by dysregulating the molecular processes of ion binding, vesicle transport and ion transport.