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

Coulter‐Mackie, Marion B.; Gagnier, Liane

doi:10.1002/(sici)1096-8628(19971128)73:1<32::aid-ajmg7>3.0.co;2-r

Cited by 12 publications

(5 citation statements)

References 17 publications

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“…Mutation D255H had been previously reported in only two unrelated Belgian patients, both compound heterozygotes carrying the IVS2+1G→A mutation on the other allele [Lissens et al, 1996] and in one heterozygote Canadian patient [Coulter-Mackie and Gagnier, 1997]. The clinical course of the disease of patient L49 (D255H/ IVS2+1G→A) in our MLD series resembled that of the patient in family 1 in the report by Lissens et al [1996], with death at 4 years of age after attempting BMT.…”

Section: Genotypephenotype Correlationsupporting

confidence: 71%

“…Several polymorphic sites have also been described within the gene Polten et al, 1991;Berger et al, 1996;Perusi et al, 1997] and some have been used to define specific haplotypes which have been associated with several mutations. Particularly interesting is the allele carrying the most prevalent mutation, IVS2+1G→A, which is in complete linkage disequilibrium with the previously described haplotype [T, G, G, G, G] for markers [BglI (842G>T), NlaIII 2 (1294G>C), NlaIII 1 (1386A>G), BsrI (2161C>G), BamHI (2213C>G)], respectively [Polten et al, 1991;Zlotogora et al, 1994;Coulter-Mackie and Gagnier, 1997].…”

Section: Introductionmentioning

confidence: 92%

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Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype–phenotype correlation studies in spanish metachromatic leukodystrophy patients

Gort¹,

Coll²,

Chabás³

1999

Hum. Mutat.

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Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic leukodystrophy (MLD), a lysosomal disorder with no specific treatment. In view of the importance of genetic counseling, analyses of mutations and polymorphisms, including the ARSA pseudodeficiency allele, were carried out in 18 unrelated Spanish MLD patients. A systematic search allowed us to identify 100% of the alleles involving 17 different mutations, 12 of which are novel: G32S, L68P, R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6-12C-->G. Two new polymorphisms, 2033C>T and 2059C>T, were identified in intron 6 which, in combination with two polymorphisms previously described (2161C>G and 2213C>G), gave rise to four different haplotypes in the control population. In addition, we also studied polymorphism 842G>T. Linkage disequilibrium was detected between mutations IVS2+1G-->A, D255H, and T327I and specific haplotypes, suggesting a unique origin for these mutations. Moreover, mutation T327I was always associated with the T allele of the new rare variant A210A (893C>T). The distribution of mutation D255H (frequency 19.4%) among patients with different MLD clinical presentation revealed a clear genotype-phenotype correlation paralleling that reported for mutation IVS2+1G-->A (frequency 25%). Among the novel mutations, only P136S and R288H occurred on a background of the ARSA pseudodeficiency allele. Screening 182 normal chromosomes identified a frequency of 8.8% of this allele; moreover, we identified two unrelated subjects with the polyA- mutation in the absence of the N350S mutation, and this infrequent haplotype reinforced the heterogeneity of conditions with ARSA deficiency.

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Section: Genotypephenotype Correlationsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 92%

Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype–phenotype correlation studies in spanish metachromatic leukodystrophy patients

Gort¹,

Coll²,

Chabás³

1999

Hum. Mutat.

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“…The A856C mutation was associated with the most common haplotype of intragenic polymorphisms, BsrI(1)-BamHI(1)-NlaIII 1 (1)-NlaIII 2 -(1). 13…”

Section: Molecular Analysismentioning

confidence: 99%

Isolated Peripheral Neuropathy in Atypical Metachromatic Leukodystrophy: A Recurrent Mutation

Coulter‐Mackie

Applegarth²,

Toone³

et al. 2002

Can. j. neurol. sci.

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Abstract:Background:Metachromatic leukodystrophy (MLD) is a genetic neurodegenerative disorder resulting from a deficiency of arylsulfatase A. Late onset forms are relatively rare. Central nervous system (CNS) involvement is characteristic at all ages.Methods:A patient in her late 40s with peripheral neuropathy was assessed by EEG, evoked potentials, CTand nerve conduction studies. Nerve and muscle biopsy samples were investigated by electron microscopy. Arylsulfatase A activity in leukocytes and excreted cerebroside sulfate were determined. The arylsulfatase A gene was investigated for mutations using polymerase chain reaction (PCR) and DNAsequencing. The identified mutation was expressed transiently in African green monkey kidney (COS) cells to determine the effect of the mutation on arylsulfatase A activity.Results:Central nervous system functions were normal. Nerve conduction velocities were decreased. Sural nerve biopsy showed inclusions typical of MLD. Arylsulfatase A was less than 5% of normal. A homozygous mutation thr286pro was identified in the arylsulfatase A gene and demonstrated to be deleterious through transient expression studies.Conclusions:Our patient has a progressive peripheral neuropathy but has apparently intact CNS function at her present age of 57 years. Biochemical, physiological and pathological findings are consistent with a diagnosis of MLD. A homozygous mutation, thr286pro, found in her arylsulfatase A gene, decreased enzyme activity to a level consistent with a late onset form of MLD.

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“…Para el gen ARSA, la mutación c.A1055G:p.N352S es una causa conocida de seudodeficiencia de arilsulfatasa. Dicho hallazgo también se correlaciona con los estudios neurometabólicos previos de la paciente 22 . POLR3A es un gen que codifica para la subunidad mayor de la ARN polimerasa iii humana 23 .…”

Section: Discussionunclassified

Neurología genómica personalizada: el futuro es ahora

Córdoba

Morón

Rodríguez-Quiroga

et al. 2014

Neurología Argentina

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

Cited by 12 publications

References 17 publications

Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype–phenotype correlation studies in spanish metachromatic leukodystrophy patients

Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: Haplotype and genotype–phenotype correlation studies in spanish metachromatic leukodystrophy patients

Isolated Peripheral Neuropathy in Atypical Metachromatic Leukodystrophy: A Recurrent Mutation

Neurología genómica personalizada: el futuro es ahora

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