Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

Abstract

Deficient arylsulfatase A activity causes the neurodegenerative disease metachromatic leukodystrophy. However, some individuals with deficient enzyme activity appear clinically normal. This "pseudodeficiency" allele commonly found among many reported populations (frequency approximately 0.10) is associated with two A-->G transitions in cis in the arylsulfatase A gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, we studied 400 individuals in the African, European, Indian and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varied from 0.01 in Indians, 0.06 in Europeans, 0.21 in East Asians to 0.32 in Africans. The frequencies of both mutations occurring together ranged from almost non-existent in the Africans and East Asians, to 0.075 in the Europeans and 0.125 in the Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and eight multi-generation families with six polymorphic enzymes showed that, of the five haplotypes found in the general population, only one was linked to the double mutations. Alleles among the four populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans whose alleles were discordant. These results are consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among the Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa at approximately 100,000-200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages.

Developing therapeutic approaches for metachromatic leukodystrophy

“…The c.*96A>G is found in the 3′ non-translated region that alters the signaling of the polyadenylation of mRNA, substantially reducing the amount of ASA produced 13. The frequency of these ARSA pseudodeficiency alleles is up to 5% in the European population 13–17. The carrier frequency of the ARSA pseudodeficiency alleles in Australia is estimated to be 20% 16.…”

Molecular and structural analysis of metachromatic leukodystrophy patients in Indian population

“…Both the pseudodeficiency alleles were found in almost equal frequency since c.1049ANG (p.Asn350Ser) allele was found in four patients and c.1524+95ANG was found in five patients ( Table 1). The frequency of pseudodeficiency allele in Indian patients (from India) is reported to be 12.5% [24]. This high frequency of the pseudodeficiency allele can be explained on the basis of selective advantage of heterozygotes.…”

An unusual arylsulfatase A pseudodeficiency allele carrying a splice site mutation in a metachromatic leukodystrophy patient

“…2 The two mutations are often found together, but, not rarely, the N350S mutation is found alone. 9 On the other hand, the *96A4G mutation has been previously found not linked to the N350S mutation only in a very limited number of cases: a subject reported by Leistner et al, 10 two sibs reported by Ricketts et al, 11 and two unrelated subjects reported by Gort et al 12 None of these subjects was an MLD patient. This is the first reported case in which the unusual pd allele containing the polyadenylation site variant but lacking the N350S variant bears a disease-causing mutation.…”