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 inARSA. The biological processes of MLD disease caused by candidate pathogenic mutations in theARSAgene 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 mutatedARSAgenes 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 anARSAc.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 mutatedARSAgenes 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,ARSAhomozygosity c.925G>A, from a Chinese MLD family. The pathogenic mechanism of theARSAmutation in MLD was identified, which may suggest new approaches to diagnosis and treatment.