title: Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity.
abstract: The occurrence of different mutations on the same arylsulfatase A allele is not uncommon, due to the high frequency of several variants, among which the pseudodeficiency mutations are particularly important. We identified a late infantile metachromatic leukodystrophy patient carrying on one allele the new E253K mutation and the known T391S polymorphism, and on the other allele the common P426L mutation, usually associated with the adult or juvenile form of the disease, and the N350S and *96A>G pseudodeficiency mutations. To analyze the contribution of mutations located on the same allele to enzyme activity reduction, as well as the possible phenotype implications, we performed transient expression experiments using arylsulfatase A cDNAs carrying the identified mutations separately and in combination. Our results indicate that mutants containing multiple mutations cause a greater reduction of ARSA activity than do the corresponding single mutants, the total deficiency likely corresponding to the sum of the reductions attributed to each mutation. Consequently, each mutation may contribute to ARSA activity reduction, and, therefore, to the degree of disease severity. This is particularly important for the alleles containing a disease-causing mutation and the pseudodeficiency mutations: in these alleles pseudodeficiency could play a role in affecting the clinical phenotype.
authors.affiliation: Laboratorio di Diagnosi Pre e Postnatale di Malattie Metaboliche, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. dppm@ospedale-gaslini.ge.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Regis
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsolini
authors.forename: Marina
authors.initials: M
authors.lastname: Stroppiano
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002553:Cerebroside-Sulfatase / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation
chemical_list: D018076:DNA, Complementary; D002553:Cerebroside-Sulfatase