Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy

Abstract

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfatase A allele carrying a E312D missense mutation and characterize the effects of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activity can be expressed from arylsulfatase A cDNAs coding for the D255H substituted enzyme, whereas Y201C and E312D mutations were associated with low amounts of residual enzyme activity. All amino acid substitutions lead to a decreased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment.

Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy

“…Though extensive information has been collected on ARSA common mutations (Polten, et al, 1991) and some studies have been performed on rare alterations (Berna, et al, 2004;Hermann, et al, 2000;Kappler, et al, 1992;Poeppel, et al, 2005), most of these latter still remain uncharacterized. In this context, functional studies on the mutated alleles, aimed at characterizing the residual enzymatic activity associated with a novel mutation, and consequently better correlating patient's genotype with phenotype, acquire a particular relevance.…”

Familial Multiple Sclerosis and Other Inherited Disorders of the White Matter

“…Generally 3 forms, early onset late infantile (1-2 years of age), juvenile (3-16 years of age), and adult form (Ͼ16 years of age) are distinguished. 59 In the most typical late infantile form, the onset of symptoms include a rapid motor and cognitive deterioration, ataxia, spastic paraparesis, leading eventually to a persistent vegetative state, and death.…”

“…In contrast to that observed in X-ALD/AMN, a genotype-phenotype correlation has been suggested in the case of ASA mutations. 59 A benign decrease in the ASA activity can be detected in 1% of the general population without MLD. Two mutations have been associated with this ASA pseudodeficiency, and the frequency of the ASA pseudodeficiency alleles is estimated to be 10% in the population.…”

Allelic Variation and Environmental Lead Exposure in Urban Children

“…It is possible that individuals who have later expression or nonexpression of the ASA allele may be affected by a less virulent form of the mutation and therefore produce residual amounts of the enzyme. 6 It is not clearly understood why some children with low levels of lead (≤20 μg/dL) show the signs of neurodeficiencies displayed by children with high levels of lead. However, the interaction between the heterozygous ASA allele and low lead exposure may be one explanation.…”

“…Although most of the ASA-deficiency MLD cases are found in the Habbanite Jewish community, approximately 12% of cases can be found in the African Americans population, and 2% in the European American population. 5,6 The heterozygous (Aa) form of ASA allelic variation and the possible interaction with environmental lead in children represent a relatively new area of toxicology research, with relatively little data at this writing. Poretz et al4 suggested that the mutant heterozygous form of the allele ASA may produce a compounded or synergistic effect of environmental lead because of the incomplete ASA enzyme activity.…”