Mucopolysaccharidosis type II: an update on mutation spectrum

Froissart, Roseline; Silva, Isabel Moreira da; Maire, I.

doi:10.1111/j.1651-2227.2007.00213.x

Cited by 82 publications

(97 citation statements)

References 40 publications

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“…Intriguingly, a third unrelated example of this R8X mutation has been reported in a patient with MPS II and this patient also has an attenuated phenotype [Vafiadaki et al, 1998;Tomatsu et al, 2006]. However, as Froissart et al (2007) have opined, the attenuated phenotype could also be explicable in terms of the proximity of the mutation to the initiation codon, a context in which nonsense-mediated decay could be circumvented, read-through of the newly introduced stop codon potentiated, or an alternative ATG translational initiation codon utilized.…”

Section: Discussionmentioning

confidence: 99%

“…The need for prognostic information, a prerequisite for making informed decisions about the most appropriate therapeutic options, has fuelled the drive to establish genotype-phenotype correlations in MPS II. Disappointingly, however, close correlations between mutant genotypes and variant clinical phenotypes have invariably been elusive, at least in part due to the inadequacy of the clinical severity scoring index routinely employed [Froissart et al, 2007]. The high incidence of CpG dinucleotide mutations in the IDS gene [Tomatsu et al, 2004] ensures that some mutations recur independently in unrelated patients (with different genetic backgrounds) but such patients often display quite divergent clinical phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…The de novo occurrence of IDS gene mutations has sometimes been demonstrated by family studies in large MPS II cohorts. While germline mosaicism has been assumed in some cases, this has only rarely been formally demonstrated [Froissart et al, 1997;Froissart et al, 2007; Moreira da Silva et al, 2001;Lin et al, 2006]. The need for prognostic information, a prerequisite for making informed decisions about the most appropriate therapeutic options, has fuelled the drive to establish genotype-phenotype correlations in MPS II.…”

Section: Introductionmentioning

confidence: 99%

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Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

et al. 2010

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Sequence analysis of the X-linked iduronate-2-sulfatase (IDS) gene in two Hunter syndrome patients revealed a lack of concordance between IDS genomic DNA and cDNA. These individuals were found to be hemizygous respectively for a nonsense mutation [c.22C>T;p.R8X] and a frameshift micro-insertion [c.10insT;p.P4Sfs] in their genomic DNA. However, both wildtype and mutant IDS sequences were evident upon cDNA analysis. Similar discrepant results were also obtained in a third unrelated patient carrying the same p.R8X mutation. Since both p.R8X mutations were inherited from carrier mothers, somatic mosaicism could be excluded. Although the presence of wild-type IDS mRNA-transcripts was confirmed in all three patients by restriction enzyme digestion, clone sequencing, pyrosequencing and single nucleotide primer extension (SNuPE), no wild-type IDS genomic sequence was detectable. The relative abundance of wild-type and mutation-bearing IDS-transcripts in different tissues was quantified by SNuPE. Although IDS transcript levels, as measured by real-time PCR, were reduced (51-71% normal) in these patients, some wild-type IDS protein was detectable by western blotting. Various possible explanations for these unprecedented findings (e.g. accidental contamination, artefactual in vitro nucleotide misincorporation, malsegregation of an extra maternal X-chromosome) were explored and experimentally excluded. PCR-based discriminant assay and segregation analysis of a linked IDS polymorphism (rs1141608) also served to exclude the presence of IDS cDNA derived from the maternal wild-type chromosome. Although it remains to be formally demonstrated by direct experimentation, the intriguing possibility arises that we have observed the in vivo correction of heritable gene lesions at the RNA level operating via a correction mechanism akin to RNA-editing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

et al. 2010

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“…Genomic rearrangements account for B20% of IDS cases. 10 There have been a number of previous reports documenting various rearrangements involving IDS and IDSP1. 8,9 Among them is a common inversion involving low-copy repeats (LCRs) in IDS intron 7 and IDSP1 that has been observed in multiple independent pedigrees.…”

Section: Introductionmentioning

confidence: 99%

“…IDSP1 is highly homologous to a 1.6-kb region within IDS intron 7 ( Figure 1c). 8,9 To date, more than 350 IDS disease-causing mutations have been described (Human Genome Mutation Database), 10 with the majority represented by missense, nonsense, splicing and small deletion mutations. Genomic rearrangements account for B20% of IDS cases.…”

Section: Introductionmentioning

confidence: 99%

LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining

et al. 2011

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Mucopolysaccharidosis type II (MPS II) is caused by mutations in the IDS gene, which encodes the lysosomal enzyme iduronate-2-sulfatase. In B20% of MPS II patients the disorder is caused by gross IDS structural rearrangements. We identified two male cases harboring complex rearrangements involving the IDS gene and the nearby pseudogene, IDSP1, which has been annotated as a low-copy repeat (LCR). In both cases the rearrangement included a partial deletion of IDS and an inverted insertion of the neighboring region. In silico analyses revealed the presence of repetitive elements as well as LCRs at the junctions of rearrangements. Our models illustrate two alternative consequences of rearrangements initiated by non-allelic homologous recombination of LCRs: resolution by a second recombination event (that is, Alu-mediated recombination), or resolution by non-homologous end joining repair. These complex rearrangements have the potential to be recurrent and may be present among those MSP II cases with previously uncharacterized aberrations involving IDS.

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Mucopolysaccharide Storage Disorders

Filocamo

Cooper

Rocco

2011

Encyclopedia of Life Sciences

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The mucopolysaccharidoses (MPSs) are a group of 11 distinct metabolic disorders that result from the deficiency of the various lysosomal enzymes required to degrade the glycosaminoglycans (GAGs) that constitute a major component of the extracellular matrix, joint fluid and connective tissue. The progressive lysosomal accumulation of GAGs ultimately impairs joint mobility and adversely affects the skeleton and cardiovascular system. Depending on the type or subtype of mucopolysaccharidosis, mental development may range from normal to profoundly impaired. Enzymatic and molecular diagnostic testing are available for all the MPSs. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are the only specific treatments for MPS currently available. Key Concepts: The degradation of glycosaminoglycans (or mucopolysaccharides) takes place in lysosomes that contain the acid hydrolases. The deficiency of any one of 11 acid hydrolases, required to normally degrade the glycosaminoglycans, gives rise to the group of lysosomal storage disorders known as the mucopolysaccharidoses. The progressive accumulation of glycosaminoglycans, a major component of the extracellular matrix, joint fluid and connective tissue, leads ultimately to multisystem involvement including organomegaly, dysostosis multiplex and abnormal facies. The observation that the fraction of lysosomal enzymes that does not enter the lysosome is secreted from the cell and can be recaptured from other cells, suggests that lysosomal storage disorders are potentially treatable by enzyme replacement therapy.

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Mucopolysaccharidosis type II: an update on mutation spectrum

Abstract: Although genotype-phenotype correlations may be difficult to establish, they will be of increasing importance for choosing the most appropriate therapy for an individual patient, as new therapeutic strategies may be targeted according to phenotype.

Cited by 82 publications

References 40 publications

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining

Mucopolysaccharide Storage Disorders

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