Arylsulfatase A pseudodeficiency-associated mutations: Population studies and identification of a novel haplotype

Ricketts, Michael H.; Goldman, David; Long, Jeffrey C.; Manowitz, Paul

doi:10.1002/(sici)1096-8628(19960726)67:4<387::aid-ajmg12>3.0.co;2-f

Cited by 20 publications

(13 citation statements)

References 25 publications

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“…In contrast, the PDg mutation must have occurred early in this history of man in the African lineage before the emergence of the PD allele with its additional PDa mutation. The current assumption is further supported by studies among the various African populations from Southern Africa (the Bantu and San; Ricketts et al 1996) in which no PD allele was found, presumably due to the absence of a North American European admixture effect in these native populations. Thus, if the additional PDa mutation occurred after the divergence of the African and non-African lineages, it must have occurred after the period of 100 000-200 000 years B.P.…”

Section: Discussionmentioning

confidence: 60%

“…An initial screening of 28 PD alleles showed no segregation of the two mutations ). This tight linkage has been confirmed in several isolated populations (Nelson et al 1991;Zlotogora et al 1994;Barth et al 1994;Ricketts et al 1996;Hohenschutz et al 1989). The frequency of the PD allele has been reported to be about 0.07-0.17 based on enzyme analyses (Herz and Bach 1984) while DNA analysis among various European populations indicated that the PD frequency ranged from 0.035 to 0.375.…”

Section: Introductionmentioning

confidence: 67%

“…According to this criterion, only the African and East Asian populations did The allele frequencies of these populations showed some clear trends. Of the 800 chromosomes sampled, there was not a single case of the polyadenylation PDa mutation occurring alone, although isolated cases have been reported before (Leistner et al 1995;Ricketts et al 1996). However, the PDg mutation was present without the PDa mutation at very high frequencies in the African (0.320) and East Asian (0.210) populations, but not in the Indians (0.01).…”

Section: Allele Frequencies Among Different Human Populationsmentioning

confidence: 95%

“…, Non-Ashkenazi Jew, and Arab populations; Nelson et al (1991) for the European-Australian (AUS.) population; Barth et al (1994) for the European-U.K. population; Ricketts et al (1996) for the European-American (Am. ), European-Finnish (Finn.…”

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confidence: 99%

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

1997

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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.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 67%

Section: Allele Frequencies Among Different Human Populationsmentioning

confidence: 95%

mentioning

confidence: 99%

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

1997

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“…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.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2003

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A late infantile metachromatic leukodystrophy patient was found to be heterozygous for the arylsulfatase A (ARSA) pseudodeficiency (pd) polyadenylation site variant (*96A4G) in the absence of the commonly associated N-glycosylation site variant (N350S). ARSA alleles were sequenced and the genotype completely defined. Six sequence variations were identified, among which two resulted as severe disease-causing mutations, both leading to the loss of the reading frame: a splice acceptor site mutation in intron 4 (849-1G4A), located on the *96A4G allele and a mononucleotide deletion (258delC) in exon 2, located on the other allele. The altered splicing caused by the 849-1G4A mutation was shown by in vitro expression of a recombinant gene containing the genomic region surrounding the mutation. Haplotype analysis of the unusual pd allele was performed in order to investigate its possible origin.

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Two new polymorphisms in the arylsulfatase A gene and their haplotype associations with normal, metachromatic leukodystrophy and pseudodeficiency alleles

Coulter‐Mackie¹,

Gagnier²

1997

Am. J. Med. Genet.

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Linkage disequilibrium exists between metachromatic leukodystrophy (MLD) and pseudodeficiency mutations and selected polymorphisms within the arylsulfatase A gene. We have identified 2 new polymorphic NlaIII sites, NlaIII1 and NlaIII2, in the gene that, when used in combination with the known BsrI and BamHI polymorphisms, extends the haplotype associations of the pseudodeficiency and the most common infantile onset MLD alleles. Fixed haplotypes have also been established for 3 other recurring MLD mutations, ala212val, pro426leu, and thr274met. The NlaIII2 site is relatively rare and was found only in association with the pseudodeficiency variant carrying the glycosylation site mutation alone.

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Arylsulfatase A pseudodeficiency-associated mutations: Population studies and identification of a novel haplotype

Cited by 20 publications

References 25 publications

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

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

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

Two new polymorphisms in the arylsulfatase A gene and their haplotype associations with normal, metachromatic leukodystrophy and pseudodeficiency alleles

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