Disease relevance of ARSA

• High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy [1].
• OBJECTIVES: To analyze mutations in the ARSA gene of a patient with adult-onset MLD with no signs of peripheral polyneuropathy and to emphasize the clinical, neuroradiologic, neuropathologic, and genetic features of the disease [2].
• It should be emphasised that whenever a cerebral MRI demonstrates the "tigroid" or "leopard-skin" demyelination pattern not only Pelizaeus-Merzbacher disease, but also metachromatic leukodystrophy diagnosis should be considered; this suggests the necessity of ARSA activity estimations in patients with such specific MRI patterns [3].
• Deficiency of arylsulfatase A or of a proteolytic product of prosaposin leads to the accumulation of cerebroside sulfate, which causes a lethal progressive demyelination [4].
• Metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA), is inherited as an autosomal recessive trait, and its frequency is estimated to be 1 in 40,000 live births [5].

Psychiatry related information on ARSA

• The aim of this study was to establish frequency of two mutations associated with ASA pseudodeficiency in healthy individuals in the Croatian population as well as in persons with Alzheimer-type dementia and Down syndrome [6].
• Arylsulfatase A activity was slightly but not significantly decreased in leukocytes derived from subjects with dementia and Down syndrome in comparison with age-matched control samples [6].
• A previous case report has suggested an association with mild-to-moderate deficiency of arylsulfatase A. We describe a 36-year-old man who recovered completely from an episode of hypoxia related to drug overdose, and 2 weeks later progressed from a confusional state to deep coma [7].

High impact information on ARSA

• To understand the molecular basis of the different forms of the disease, we analyzed arylsulfatase A alleles associated with metachromatic leukodystrophy [8].
• The clinical variability can be explained by the different levels of residual arylsulfatase A activity associated with these genotypes [8].
• We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas [9].
• Arylsulfatase A and B activities were found to be reduced in the presence of ascorbic acid in all normal and osteoarthritic cell lines examined when measured 3, 6, 10, and 13 days after the introduction of the vitamin in the culture medium [10].
• Arylsulfatase B was separated from arylsulfatase A in extracts of human lung tissue by anion exchange chromatography and further purified by gel filtration and cation exchange chromatography [11].

Chemical compound and disease context of ARSA

• An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A [12].
• Metachromatic leukodystrophy is a lysosomal storage disease caused by deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of an Ashkenazi Jewish patient suffering from the severe late infantile form of the disease revealed a point mutation in exon 2 causing proline 136 to be substituted by leucine [13].
• We measured the following enzymatic activities: alpha-l-iduronidase (Hurler), galactocerebrosidase (globoid cell leuko- dystrophy) and arylsulfatase A (metachromatic leukodystrophy) [14].
• Lymphoid cells derived from patients with metachromatic leukodystrophy showed a severe deficiency in cerebroside sulfatase activity, as measured using radiolabelled sulfatide, but some residual activity of arylsulfatase A when measured with the chromogenic substrate, para-nitrocatechol sulfate [15].
• The arylsulfatase A defect in metachromatic leukodystrophy cells could be demonstrated on focused fractions even using the artificial substrates, para-nitrocatechol sulfate and 4-methylumbelliferyl sulfate [15].

Biological context of ARSA

• A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD [16].
• An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy [17].
• Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products [17].
• We report the findings of clinical evaluation and neurophysiologic and neuropathologic studies of peripheral nerves; we also performed DNA sequence analysis, transfections, metabolic labeling, and immunoprecipitation of mutant ARSA polypeptides [2].
• 1. This region contains a linkage group that maps to mouse chromosome 15, region E, and includes the SIS, ARSA, and DIA 1 genes [18].

Anatomical context of ARSA

• The mutant ARSA is correctly targeted to the lysosomes but is unstable [1].
• The expression of the mutant ARSA protein may be influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others [1].
• Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene [2].
• The segregation of the chromosome 22 markers ACO2, ARSA, and NAGA was studied in somatic cell hybrid clones [19].
• While ARSA, ARSB, and PAS are water-soluble enzymes, ES has a hydrophobic domain and is presumed to be bound to the endoplasmic reticulum membrane [20].

Associations of ARSA with chemical compounds

• In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity [16].
• It is proposed that histidine 229 protonates the leaving alcoholate after hydrolysis.C69S-ASA is able to bind covalently to the substrate and hydrolyze it, but is unable to release the resulting sulfate [21].
• Arylsulfatase A (ASA) belongs to the sulfatase family whose members carry a C(alpha)-formylglycine that is post-translationally generated by oxidation of a conserved cysteine or serine residue [21].
• This suggests that the double conformation observed in the structure of wild-type ASA is more likely to correspond to a formylglycine hydrate than to a twofold disordered aldehyde oxo group, and accounts for the relative inertness of the C69S-ASA mutant [21].
• The structure of C69S-ASA shows the serine side-chain in a single conformation, turned away from the position a substrate occupies in the complex [21].

Regulatory relationships of ARSA

• Furthermore, the uptake of the lysosomal enzyme arylsulfatase A and of a Man-6-P neoglycoprotein is stimulated 2-3-fold by IGF I and IGF II, and this effect persists for at least 6 h [22].

Other interactions of ARSA

• Among the recombinant enzymes only the endoplasmic reticulum-associated ARSC showed activity toward iodothyronine sulfates; the soluble lysosomal ARSA and ARSB were inactive [23].
• One cosmid, representing a region coding for an ubiquitous 300-bp transcript, is localized 600 kb from PDGFB, and four cosmids contained sequences surrounding the ARSA gene at 22q13 [24].
• Regional localization of the genes coding for human ACO2, ARSA, and NAGA on chromosome 22 [19].
• The results suggest the assignment of ARSA and NAGA to the region 22q13 leads to 22qter and of ACO2 to the region 22q11 leads to 22q13 [19].
• The human genome contains six arylsulfatase genes (ARSA-ARSF), of which four are clustered in a distal region of the short arm of the X chromosome (Xp22.3) [25].

Analytical, diagnostic and therapeutic context of ARSA

• Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity [26].
• Negligible amounts of ARSA mRNA were observed in Northern blots [27].
• First, measurements of FRSA and ARSA were performed from data obtained during a graded and maximal exercise test [28].
• In this multicentre study, we examined the prevalence of two mutations in the arylsulfatase A (ARSA) gene, i.e., c.459+1G>A and p.P426L, in 384 unrelated European patients presenting with different types of metachromatic leukodystrophy (MLD) [29].
• Thus, these results show the promising potential of developing an ARSA delivery system to the CNS based on the use of a polymer-encapsulated transduced xenogenic cell line for gene therapy of MLD [30].

References