Novel type of genetic rearrangement in the iduronate-2-sulfatase (IDS) gene involving deletion, duplications, and inversions

Karsten, Stanislav L.; Voskoboeva, Elena; Krasnopolskaja, Xcenia; Bondeson, Marie-Louise

doi:10.1002/(sici)1098-1004(199912)14:6<471::aid-humu5>3.0.co;2-5

Cited by 8 publications

(7 citation statements)

References 22 publications

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“…About 20% of cases are due to major events, in particular, rearrangements caused by homologous recombination with IDS-2 locus [see Karsten et al, 1999]. Failure to find mutations is probably due to overlooking them [Goldenfum et al, 1996], so I use P in (1).…”

Section: Ids Mucopolysaccharidosistype II (Mps Ii)mentioning

confidence: 99%

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

2002

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Communicated by Steve S. Sommer I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X-linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8 Â 10 À8 per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are B25 times more common than all other mutations, deletions are Bthree times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5 Â 10 À7 make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level. Hum Mutat 21:12-27,

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Section: Ids Mucopolysaccharidosistype II (Mps Ii)mentioning

confidence: 99%

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

2002

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“…11 Also reported are large deletions of the IDS locus ranging from single or multiple exon deletions to deletions of the entire gene, with or without the involvement of neighboring genes. Complex rearrangements reported previously include recombination between the IDS gene and the IDSP1 pseudogene, 8,9 a deletion with an inverted duplication, 12 and an Alu-mediated deletion with an insertion. 13 In particular, two highly homologous regions within IDS and IDSP1 appear to facilitate intrachromosomal recombination events leading to complex rearrangements.…”

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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“…Although most of the causative mutations of Hunter disease occur in the IDS gene, located in Xq28 region (Wilson et al 1993), various deletions and gene rearrangements may also occur within a pseudogene (IDS-2), located 20 kb telomeric to the gene (Bunge et al 1998;Karsten et al 1999;Lagerstedt et al 1997;Timms et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations

Alves¹,

Mangas²,

Prata

et al. 2006

J of Inher Metab Disea

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Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal storage disease caused by a defect in the iduronate-2-sulfatase gene (IDS). Alternative splicing of the IDS gene can occur and the underlying regulatory mechanism may be rather complex. Nevertheless, little information is available on the role of variations at the IDS locus in the splicing process. Here we report that splice mutations at the IDS locus are an important source of MPS II pathogenicity, accounting for almost 56% of Portuguese cases. Among 16 unrelated Portuguese MPS II patients, 15 different mutations were identified: six intronic splice mutations (c.104-2AG, c.241-2A>G, c.241-1G>A, c.418+1G>A, c.880-8AG and c.1181-1G>C); two exonic splice mutations (c.1006G>lC and c.1122C>T); five missense mutations (D269V, D69V, D148N, R88C and P86L); one nonsense mutation (Q465Ter); one total IDS gene deletion; and one rearrangement involving a IDS gene inversion. Furthermore, nine of the 15 detected mutations affected the usual splicing pattern at the locus. Some of them are responsible for dramatic changes in the splicing mechanism. For example, the substitution mutation, c.418+1G>A, revealed the presence of an exonic sequence inside intron 3. Our study provides evidence that the IDS locus is prone to splicing mutations and that such susceptibility is particularly high in exon 3 and neighbouring regions. Consequently, mutation screening of the IDS gene cannot be restricted to gDNA examination. Unless cDNA analysis is also conducted, misclassifications as silent or missense mutations can be produced and even uncharacteristic splice-site mutations can be misinterpreted as classic splicing defects that may generate severe, unconventional splicing alterations.

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Novel type of genetic rearrangement in the iduronate-2-sulfatase (IDS) gene involving deletion, duplications, and inversions

Cited by 8 publications

References 22 publications

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

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

Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations

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