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

Abstract

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.

Mutation Update ofARSAandPSAPGenes Causing Metachromatic Leukodystrophy

“…A description of the methods for ARSA variant detection and analysis can be found in Supp. Methods and in Biffi et al (2008), Grossi et al (2008), Regis et al (1995Regis et al ( , 1997Regis et al ( , 2004.…”

Gain-of-glycosylation mutations

“…Cells from patients with CDG affecting protein maturation display impairments in the glycosylation of multiple target proteins [3]. Other pathogenic mutations have been described that lead to a loss of glycosylation of specific proteins encoded by the mutated genes [4][5][6][7][8][9][10], further illustrating the importance of glycosylation in human physiology. Indeed, such mutations have been reported in many different genes, suggesting that glycosylation might actually be required for the optimal function of most glycosylated proteins.…”

Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism

“…Hub genes with high connectivity may have more important biological significance in modules. 43 PPI network analysis is an effective tool for revealing the principles of cellular organizations and functions. In this study, PPI analysis showed that the mutation of c.925G (c.925G>A, c.925G>T, c.925G>C) had more protein complexes that might interact than the control group.…”