Identification of a novel mutation in ARSA gene in patients with metachromatic leukodystrophy disorder

Introduction: Metachromatic leukodystrophy (MLD, OMIM 250100) is a severe neurodegenerative disorderinherited in an autosomal recessive pattern. It is caused by deficiency of arylsulfatase A (ARSA, EC 3.1.6.8)protein. The deficiency results in the accumulation of glycolipid cerebroside sulfate in the myelin membranes ofthe central and peripheral nervous system. Three clinical subtypes of MLD have been distinguished based on theage of onset: infantile (severe between 0-2 years), juvenile (3-16 years), and late onset (after sexual maturity).Here in we describe two unrelated Iranian affected patients with a new pathogenic mutation not reported before.Material and Methods: Blood samples were collected from patients and relative members of their family.Genomic DNA was isolated based on salting out method. Direct sequencing was done for all of the exons of theARSA gene. Potential mutations were defined by exclusion from the previously reported mutations in PubMedand other databases. We used PolyPhen-2 to predict the potential impact of the new mutations on proteinfunction and structure.Result: Sequence analysis demonstrated three benign mutations in intronic region of ARSA gene(2059(C> T), 2213 (C> G), 1788 A> G ), two benign mutations, c.*96A> G and p.Asn352Ser, in exonic and 3UTRrespectively, associated with ARSA pseudo deficiency (low residual ARSA activity but clinically healthycondition) and one pathogenic mutation p.pro 192 Arg.Conclusion: The mutation p.pro 192 Arg with pathogenic effect on ARSA linked with benign mutations (2059C> T), 2213 (C> G), 1788 A> G ), c.*96A> G and p.Asn352Ser, detected in homozygous status in affectedindividuals and in heterozygous status in their parents.

کلیدواژه ها:

Metachromatic leukodystrophy ، Neurodegenerative ، Pathogenic mutation