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

Background Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disorder caused by mutations in ARSA . The biological processes of MLD disease caused by candidate pathogenic mutations in the ARSA gene remain unclear. Methods We 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 analyze the potential pathogenesis of the identified mutations. Overexpression cell models of wild‐type and mutated ARSA genes were constructed. The accumulated sulfatides and expression profiles in the cell models were detected, and a series of bioinformatics analyses were carried out to compare the biological changes caused by the candidate pathogenic mutations. Results We identified an ARSA c.925G>A homozygous mutation from a Chinese late‐infantile MLD patient, the first report of this mutation in East Asia. The literature and protein structure analysis indicated that three types of mutations at c.925G (c.925G>A, c.925G>T, c.925G>C) were pathogenic. The overexpression of wild‐type or mutated ARSA genes influenced the accumulation of sulfatides. The co‐expression modules in the mutated cell models were constructed by genes related to calcium signaling and vesicle transport. Conclusion Our results identified a pathogenic mutation, ARSA homozygosity c.925G>A, from a Chinese MLD family. The pathogenic mechanism of the ARSA mutation in MLD was identified, which may suggest new approaches to diagnosis and treatment.