%0 Journal Article %J Hum Mutat %D 1998 %T DNA deletion confined to the iduronate-2-sulfatase promoter abolishes IDS gene expression. %A Timms, K M %A Huckett, L E %A Belmont, J W %A Shapira, S K %A Richard A Gibbs %K Base Sequence %K Child, Preschool %K DNA Mutational Analysis %K Gene Expression Regulation %K Humans %K Iduronate Sulfatase %K Male %K Molecular Sequence Data %K Mucopolysaccharidosis II %K Pedigree %K Phenotype %K Promoter Regions, Genetic %K Sequence Analysis, DNA %K Sequence Deletion %X

Deficiency of the enzyme iduronate-2-sulfatase (IDS) results in Hunter syndrome, an X-linked recessive lysosomal storage disorder. In this study, analysis of a patient with features of moderate to severe Hunter syndrome identified a 178-bp deletion upstream of IDS exon 1 spanning a predicted promoter element. Sequencing of all nine IDS exons from this patient failed to identify any additional mutations within the coding regions or in intron-exon boundaries. The 178-bp deletion is flanked by two 13-bp direct repeats and potential DNA topoisomerase II recognition sites. These findings point toward nonhomologous recombination as a possible mechanism for this mutation. Expression studies on this patient do not detect any IDS transcripts, indicating that the deletion spans sequences essential for IDS expression. Complete lack of expression of IDS is consistent with the moderate to severe phenotype observed in this patient.

%B Hum Mutat %V 11 %P 121-6 %8 1998 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/9482575?dopt=Abstract %R 10.1002/(SICI)1098-1004(1998)11:2<121::AID-HUMU4>3.0.CO;2-M %0 Journal Article %J Gene %D 1998 %T The genomic organization of Isopeptidase T-3 (ISOT-3), a new member of the ubiquitin specific protease family (UBP). %A Timms, K M %A Ansari-Lari, M A %A Morris, W %A Brown, S N %A Richard A Gibbs %K Amino Acid Sequence %K Animals %K Base Sequence %K Carbon-Nitrogen Lyases %K Chromosome Mapping %K Chromosomes, Human, Pair 3 %K Consensus Sequence %K DNA, Complementary %K Exons %K Female %K Gene Library %K Humans %K Male %K Mice %K Molecular Sequence Data %K Organ Specificity %K Ovary %K Polymerase Chain Reaction %K Recombinant Proteins %K Saccharomyces cerevisiae %K Sequence Alignment %K Sequence Homology, Amino Acid %K Substrate Specificity %K Testis %K Ubiquitins %X

A novel Isopeptidase T gene (ISOT-3) has been identified on human mosome 3q26.2--q26.3. gene shows 67.3% nucleotide identity and 54.8% amino acid identity to n Isopeptidase (ISOT-1). Northern blot analysis has shown that ISOT-3 is highly essed in ovary and testes, low-level expression in six other tissues tested. In contrast, ISOT-1 is essed at high levels in brain, and there is no detectable expression in ovary. The exonic nization of these two genes highly conserved with only one variant intron position. Intron 15 in -3 is absent in ISOT-1, there is an alternate splice site at the same location. Although the --intron structure has been erved between the two genes, ISOT-3 has significantly larger intronic ons, and the overall of this gene is at least 90 kb compared to 15 kb for ISOT-1. These data suggest that both ISOT-1 and ISOT-3 have descended from a common ancestor. In addition, the low overall sequence identity and different expression patterns may reflect differences in substrate specificity.

%B Gene %V 217 %P 101-6 %8 1998 Sep 14 %G eng %N 1-2 %1 https://www.ncbi.nlm.nih.gov/pubmed/9841226?dopt=Abstract %R 10.1016/s0378-1119(98)00341-2 %0 Journal Article %J Hum Mol Genet %D 1997 %T Molecular and phenotypic variation in patients with severe Hunter syndrome. %A Timms, K M %A Bondeson, M L %A Ansari-Lari, M A %A Lagerstedt, K %A Donna M Muzny %A Dugan-Rocha, S P %A Nelson, D L %A Pettersson, U %A Richard A Gibbs %K Chromosome Mapping %K Cloning, Molecular %K Electrophoresis, Agar Gel %K Gene Deletion %K Gene Expression %K Gene Rearrangement %K Humans %K Iduronate Sulfatase %K Male %K Molecular Sequence Data %K Mucopolysaccharidosis II %K Nuclear Proteins %K Phenotype %K Polymerase Chain Reaction %K Proteins %K Pseudogenes %K Recombination, Genetic %K Seizures %K Trans-Activators %K X Chromosome %X

Severe Hunter syndrome is a fatal X-linked lysosomal storage disorder caused by iduronate-2-sulphatase (IDS) deficiency. Patients with complete deletion of the IDS locus often have atypical phenotypes including ptosis, obstructive sleep apnoea, and the occurrence of seizures. We have used genomic DNA sequencing to identify several new genes in the IDS region. DNA deletion patients with atypical symptoms have been analysed to determine whether these atypical symptoms could be due to involvement of these other loci. The occurrence of seizures in two individuals correlated with a deletion extending proximal of IDS, up to and including part of the FMR2 locus. Other (non-seizure) symptoms were associated with distal deletions. In addition, a group of patients with no variant symptoms, and a characteristic rearrangement involving a recombination between the IDS gene and an adjacent IDS pseudogene (IDS psi), showed normal expression of loci distal to IDS. Together, these results identify FMR2 as a candidate gene for seizures, when mutated along with IDS.

%B Hum Mol Genet %V 6 %P 479-86 %8 1997 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/9147653?dopt=Abstract %R 10.1093/hmg/6.3.479