ClinVar Genomic variation as it relates to human health

In an individual homozygous for the ARSA pseudodeficiency (250100) allele, Gieselmann et al. (1989) found 2 A-to-G transitions: one changed asn350 to serine, leading to loss of an N-glycosylation site (607574.0002). This loss explained the smaller size of ARSA in ARSA pseudodeficient fibroblasts. Introduction of ser350 into normal ARSA cDNA did not affect the rate of synthesis, stability, or catalytic properties of ARSA in stably transfected baby hamster kidney cells, however. The other A-to-G transition changed the first polyadenylation signal downstream of the stop codon from AATAAC to AGTAAC. The latter change caused a severe deficiency of a 2.1-kb RNA species. The deficiency of the 2.1-kb RNA species explained the diminished synthesis of ARSA in pseudodeficiency fibroblasts. The same change was found in 4 unrelated individuals with pseudodeficiency. In those who are homozygous for the pseudodeficiency allele or carry it in heterozygous state with a normal allele, enough arylsulfatase A is synthesized to prevent clinically apparent disease. In combination with other mutant alleles, it may cause metachromatic leukodystrophy. Nelson et al. (1991) likewise found the A-to-G change at nucleotide 1620 in the first polyadenylation signal of the ARSA gene resulting in loss of its major mRNA species and a greatly reduced level of enzyme activity. This change was found to be closely linked to another A-to-G transition at nucleotide 1049 which changed asparagine-350 to serine but did not affect ARSA activity. The findings of Nelson et al. (1991) supported the conclusion of Gieselmann et al. (1989) that the change in nucleotide 1620 is always associated with that at nucleotide 1049. Barth et al. (1994) stated that the 2 mutations do not always occur together and that at least the N350S mutation may be found alone. The carrier frequency of the ARSA pseudodeficiency mutation in Australia was estimated to be about 20%. Li et al. (1992) described a polymerase chain reaction (PCR)-based method for genotypically identifying pseudodeficiency. Barth et al. (1994) used PCR and restriction endonuclease digestion to determine the frequency of A-to-G transitions at bases 1049 (N350S) and 1620 in healthy persons from England. Mutations were found in 24 of 77 screened persons. Two were homozygous for both mutations, 16 were heterozygous for both, 5 were heterozygous for the N350S mutation alone, and 1 was homozygous for the N350S mutation. Study of the 16 persons heterozygous for both mutations showed that in 15 persons both mutations were located on the same chromosome, and in 1 person the mutations were located on different chromosomes. Persons homozygous for both mutations had the lowest activities of ARSA. Harvey et al. (1998) presented evidence that the combined effect of reduction in ARSA mRNA due to the polyadenylation defect and the lowering of ARSA activity and aberrant targeting of the expressed N350S ARSA protein (607574.0002) to the lysosome was estimated to reduce ARSA activity in pseudodeficiency homozygotes to approximately 8% of normal. (less)