{"gene":"IDS","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"The IDS gene encoding iduronate-2-sulfatase spans approximately 24 kb and is split into nine exons. The promoter lacks a TATA box but contains GC box consensus sequences, consistent with housekeeping gene regulation.","method":"Genomic cloning and sequencing of overlapping genomic clones; promoter region analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing of the entire gene structure from overlapping genomic clones, foundational structural characterization replicated in subsequent studies","pmids":["8244397"],"is_preprint":false},{"year":1995,"finding":"Inversion of the IDS gene resulting from recombination between homologous sequences in intron 7 of IDS and sequences near exon 3 of the IDS-related locus (IDS-2/IDSP1), located within 90 kb telomeric of IDS, is a common cause (~13%) of Hunter syndrome. No deletions or insertions accompany the recombination.","method":"Southern blot analysis and nucleotide sequencing of rearrangement junctions in Hunter syndrome patients","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing of recombination junctions in multiple patients, replicated across multiple studies","pmids":["7633410"],"is_preprint":false},{"year":1995,"finding":"An IDS-related locus (IDS-2/IDSP1) exists within 80 kb telomeric of the functional IDS gene on Xq28, containing sequences homologous to exons 2 and 3 and introns 2, 3, and 7 of IDS (exon 3 sequences show 100% identity). This locus complicates mutational analysis of genomic DNA from Hunter syndrome patients.","method":"Southern blot analysis, PCR amplification, and sequencing to map homologous sequences","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequencing and Southern blot characterization, independently confirmed in multiple subsequent studies","pmids":["8528670"],"is_preprint":false},{"year":1992,"finding":"Structural alterations (large deletions and major rearrangements) in the IDS gene were found in ~20% of MPS-II patients. A region within IDS is prone to structural alterations, with six of seven rearrangements showing similar or identical Southern blot patterns, suggesting a recombination hotspot.","method":"Southern blot analysis of 46 unrelated MPS-II patients using a full-length IDS cDNA probe; deletion breakpoint mapping with flanking markers","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Southern blot with multiple patients, single lab, two orthogonal approaches (hybridization + flanking markers)","pmids":["1303177"],"is_preprint":false},{"year":1995,"finding":"An alternative 1.4-kb IDS transcript was identified that encodes a protein identical to full-length IDS except for the absence of the 207-amino-acid C-terminal domain, which is replaced by 7 amino acids, suggesting possible existence of an additional IDS enzyme form.","method":"cDNA cloning and sequencing of alternative transcript","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, cDNA cloning and sequencing; functional significance not established","pmids":["8530090"],"is_preprint":false},{"year":1997,"finding":"IDS is processed from two precursor forms (76 and 90 kDa) through a series of intermediate forms to mature 55- and 45-kDa polypeptides in fibroblasts, COS cells, and lymphoblastoid cell lines. Transfer of IDS from overexpressing cells to IDS-deficient cells occurs preferentially by cell-to-cell contact rather than through secreted enzyme, as IDS precursors are poorly secreted. The 76- and 62-kDa transferred IDS polypeptides are correctly processed to the mature 55- and 45-kDa forms in recipient fibroblasts.","method":"Western blotting of IDS processing in multiple cell lines; coculture and conditioned medium transfer experiments with transfected cells and IDS-deficient fibroblasts","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization of processing steps and transfer mechanism using multiple cell lines and orthogonal experimental approaches (coculture vs. conditioned medium)","pmids":["9024795"],"is_preprint":false},{"year":1996,"finding":"An intragenic IDS deletion (removing exons IV–VII) results from gene-pseudogene exchange between highly homologous regions in intron 3 and intron 7 of IDS and the IDS-2 pseudogene, producing a rearranged gene with junction intron containing pseudogene intron 3- and intron 7-related sequences.","method":"Southern blot and PCR characterization of deletion junctions; sequencing of breakpoint regions","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct sequencing of recombination junctions, single lab, two patients","pmids":["8807335"],"is_preprint":false},{"year":1997,"finding":"Two distinct deletions in the IDS gene region, separated by 30 kb, result from non-homologous (illegitimate) recombination events between short direct repeats. The heptamer sequence 5'-TACTCTA-3' is present at both deletion junctions, suggesting it is a recombination hotspot.","method":"Southern blot, PCR, and nucleotide sequencing of deletion junctions","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct sequencing confirming recombination mechanism at both junctions, single case study","pmids":["9244428"],"is_preprint":false},{"year":2006,"finding":"Point mutations in the IDS gene can activate multiple cryptic splice sites. Mutations at invariant splice-site motifs (c.418+1G>C) produce only aberrantly spliced transcripts, while mutations in variant motifs (c.419G>T) or coding regions (c.245C>T) lead to a mixture of aberrant and correctly spliced transcripts. Nonsense-mediated mRNA decay (NMD) reduces mRNA levels for some aberrant transcripts.","method":"RT-PCR cloning and sequencing of transcripts; real-time RT-PCR quantification of mRNA levels; computational analysis of splice site scores","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RT-PCR characterization of aberrant transcripts combined with quantitative real-time PCR, multiple patients studied","pmids":["16699754"],"is_preprint":false},{"year":2006,"finding":"Splice mutations in the IDS gene account for ~56% of MPS II cases in a Portuguese cohort. Mutations affecting the splicing of exon 3 are particularly common, and some mutations cause dramatic changes in splicing mechanism including revelation of a cryptic exonic sequence inside intron 3. cDNA analysis is required alongside gDNA analysis to correctly classify IDS mutations.","method":"Genomic DNA sequencing and cDNA analysis by RT-PCR in 16 unrelated MPS II patients","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal gDNA and cDNA analyses in a cohort of patients establishing splicing mechanism","pmids":["17063374"],"is_preprint":false},{"year":2006,"finding":"Nonsense and nonstop mutations in IDS lead to reduced mRNA levels via nonsense-mediated decay (NMD) and nonstop mRNA decay pathways, respectively, as measured by real-time RT-PCR. Two mutations (Q66X and V136fs75X) produced transcripts evading mRNA surveillance despite fulfilling the known criteria, showing variability in NMD susceptibility at the IDS locus.","method":"Real-time RT-PCR quantification of IDS mRNA levels; characterization of 17 patient alleles","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative real-time RT-PCR used systematically across multiple alleles to assess mRNA decay pathways","pmids":["16495038"],"is_preprint":false},{"year":2009,"finding":"Systemic AAV-mediated delivery of hIDS in MPSII mice results in high circulating IDS levels that cross the blood-brain barrier and correct CNS glycosaminoglycan accumulation and CNS defects. The CNS correction arises from the enzyme crossing the BBB, not from brain transduction.","method":"Systemic injection of AAV2/5CMV-hIDS in MPSII mouse pups; biochemical and histological assessment of visceral organs and brain at up to 18 months post-treatment","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with long-term follow-up, biochemical and histological outcomes, BBB crossing established by comparing brain transduction vs. circulating enzyme","pmids":["19679226"],"is_preprint":false},{"year":2011,"finding":"The synonymous IDS mutation c.879G>A (p.Gln293Gln) activates a cryptic splice site, causing a 28-bp deletion and premature termination at p.Tyr285GlufsX47, demonstrating that silent variants can cause pathogenic splicing alterations in the IDS gene.","method":"RT-PCR and Sanger sequencing of cDNA from patient fibroblasts; X-inactivation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RT-PCR and sequencing directly demonstrating aberrant splicing at RNA level, complemented by X-inactivation analysis","pmids":["21829674"],"is_preprint":false},{"year":2011,"finding":"Complex rearrangements at the IDS locus initiated by non-allelic homologous recombination between IDS and the nearby pseudogene IDSP1 (a low-copy repeat) can be resolved either by Alu-mediated recombination or by non-homologous end joining, producing partial deletion plus inverted insertion configurations.","method":"Southern blot, PCR, and in silico analysis of repetitive elements at rearrangement junctions in two MPS II patients","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct sequencing and in silico analysis of two cases, mechanistic model proposed but not experimentally reconstituted","pmids":["21593745"],"is_preprint":false},{"year":2015,"finding":"SRSF2 and hnRNP E1 may be involved respectively in activation and repression of the constitutive 3' splice site of IDS exon 3 (established by minigene and overexpression assays for mutations c.241C>T and c.257C>T). Antisense morpholino oligonucleotides and locked nucleic acids targeting the c.1122C>T aberrant splice site in exon 8 failed to abolish the abnormal transcript and instead generated additional aberrant splicing products, indicating that the oligonucleotides masked a cis-acting element required for normal 5' splice site regulation.","method":"Cell-based splicing assays with mutant minigenes; overexpression assays; transfection of antisense oligonucleotides in patient and control fibroblasts","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene and overexpression assays in cell lines, antisense oligonucleotide experiments in patient fibroblasts; single lab","pmids":["26407519"],"is_preprint":false},{"year":2016,"finding":"Homology modeling of IDS missense variants predicts that the P120R substitution (severe MPS II) deforms an α-helix (I119–F123), causing major structural alteration, whereas N534I (attenuated MPS II) has marginal structural effect. Expression studies of nine IDS variants showed impaired enzymatic activity and aberrant intracellular processing (by immunoblotting) irrespective of phenotype.","method":"Homology modeling of IDS structure; expression studies with immunoblotting for intracellular processing; IDS enzyme activity assays in patient-derived cells","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical activity and processing assays combined with structural modeling; single lab","pmids":["27246110"],"is_preprint":false},{"year":2017,"finding":"Expression studies of IDS variants demonstrated impaired enzymatic activity and aberrant intracellular processing; total deletion of IDS invariably results in neuronopathic MPS II phenotype. Low or cell-type-specific residual IDS activity may be sufficient to prevent the neuronal phenotype.","method":"IDS enzyme activity assays; immunoblotting for IDS protein processing; quantification of urinary glycosaminoglycans by mass spectrometry in a cohort of Dutch MPS II patients","journal":"Developmental medicine and child neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity and immunoblotting in a defined cohort; single lab with multiple orthogonal readouts","pmids":["28543354"],"is_preprint":false},{"year":2019,"finding":"In vitro expression studies of novel IDS missense mutations showed significantly decreased IDS enzymatic activity. Western blotting demonstrated that examined mutations produce IDS precursor protein at similar or slightly lower molecular mass without detectable mature forms, indicating impaired post-translational processing.","method":"Transient expression studies; IDS enzyme activity assay; Western blotting of transfected cells","journal":"Clinica chimica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays with enzyme activity and Western blotting; single lab","pmids":["30639582"],"is_preprint":false},{"year":2019,"finding":"IDS-loaded brain-targeted PLGA nanoparticles (g7-NPs) deliver functional IDS enzyme to fibroblasts from MPS II patients, restoring IDS activity to levels comparable to healthy cells and reducing GAG content to non-pathological levels. In MPSII mice, weekly g7-NPs-IDS administration reduced GAG deposits and neuroinflammatory markers in both liver and brain tissues.","method":"In vitro IDS activity assay in patient fibroblasts; in vivo biochemical, histological, and immunohistochemical assessment in MPSII mouse model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with direct biochemical and histological readouts; single lab","pmids":["31022913"],"is_preprint":false},{"year":2010,"finding":"Wild-type IDS mRNA transcripts were detected in the cDNA of three Hunter syndrome patients carrying IDS nonsense or frameshift mutations in genomic DNA, with no wild-type IDS genomic sequence detectable. Multiple methods (restriction enzyme digestion, clone sequencing, pyrosequencing, SNuPE, real-time PCR, Western blotting) confirmed both the mutant genomic sequence and the presence of some wild-type IDS protein, suggesting possible in vivo RNA-level correction of the mutations.","method":"Restriction enzyme digestion, clone sequencing, pyrosequencing, SNuPE, real-time PCR, Western blotting; segregation analysis of linked IDS polymorphism to exclude maternal X-chromosome contamination","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods confirming the finding in three patients; proposed mechanism (RNA editing) not directly proven","pmids":["20104590"],"is_preprint":false},{"year":2019,"finding":"In vitro expression studies of novel IDS missense mutations (c.137A>C, c.311A>T, c.454A>C, c.797C>G, c.817C>T, c.998C>T, c.1106C>G, c.1400C>T, c.1402C>T, c.1403G>A) showed significantly decreased IDS enzymatic activity, establishing their pathogenic nature.","method":"In vitro IDS activity assay in transiently transfected cells expressing novel IDS variants","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro enzyme activity assays across multiple novel variants; single lab","pmids":["31877959"],"is_preprint":false}],"current_model":"IDS (iduronate-2-sulfatase) is a lysosomal enzyme encoded by a 9-exon, ~24-kb X-linked gene (Xq28) that degrades heparan sulfate and dermatan sulfate; it is synthesized as 76–90 kDa precursor forms that are processed through intermediate forms to mature 55- and 45-kDa polypeptides, with transfer between cells occurring preferentially by cell-to-cell contact; ~13–20% of MPS II mutations arise from recombination-driven inversions or deletions between IDS and the nearby pseudogene IDSP1 at established hotspots (intron 7/exon 3 region), while point mutations frequently cause aberrant splicing by activating cryptic splice sites, and some nonsense/frameshift alleles undergo nonsense-mediated mRNA decay; circulating IDS enzyme can cross the blood-brain barrier to correct CNS glycosaminoglycan accumulation in mouse models, a property exploited therapeutically."},"narrative":{"mechanistic_narrative":"IDS encodes iduronate-2-sulfatase, a lysosomal sulfatase whose deficiency causes the X-linked lysosomal storage disorder mucopolysaccharidosis type II (Hunter syndrome) [PMID:19679226, PMID:28543354]. The gene spans ~24 kb across nine exons and is driven by a TATA-less, GC-box-containing promoter characteristic of housekeeping genes [PMID:8244397]. The enzyme is synthesized as 76- and 90-kDa precursors that are post-translationally processed through intermediate forms to mature 55- and 45-kDa polypeptides; because precursors are poorly secreted, IDS transfers to enzyme-deficient cells preferentially by cell-to-cell contact, after which the transferred polypeptides are correctly matured in recipient cells [PMID:9024795]. Pathogenic missense variants typically retain only precursor protein with impaired or absent maturation and reduced catalytic activity, and total loss of IDS produces the neuronopathic phenotype while low residual activity can spare the CNS [PMID:28543354, PMID:30639582, PMID:31877959]. A major share of disease-causing alleles arise from genomic rearrangement: non-allelic homologous recombination between IDS and the adjacent IDSP1 (IDS-2) pseudogene ~80–90 kb telomeric on Xq28—whose exon 3 sequence is 100% identical to IDS—drives recurrent inversions and intragenic deletions at intron 7/exon 3 hotspots [PMID:7633410, PMID:8528670, PMID:8807335], while additional rearrangements occur through illegitimate recombination at short direct-repeat hotspots [PMID:9244428, PMID:21593745]. A second large class of mutations, including synonymous variants, disrupts splicing by activating cryptic splice sites and engaging nonsense-mediated and nonstop mRNA decay [PMID:16699754, PMID:17063374, PMID:21829674]. The capacity of circulating IDS to cross the blood-brain barrier and correct CNS glycosaminoglycan accumulation has been exploited therapeutically in mouse models [PMID:19679226].","teleology":[{"year":1993,"claim":"Establishing the genomic architecture and promoter character of IDS defined the gene as a constitutively expressed locus and provided the structural framework for all subsequent mutation analysis.","evidence":"Genomic cloning, sequencing of nine exons, and promoter analysis","pmids":["8244397"],"confidence":"High","gaps":["Does not address protein structure or catalytic mechanism","No functional confirmation of housekeeping expression in vivo"]},{"year":1992,"claim":"Detection of large deletions and rearrangements in ~20% of MPS II patients revealed that a region of IDS is structurally unstable, pointing to a recombination hotspot before its mechanism was known.","evidence":"Southern blot of 46 unrelated MPS-II patients with full-length cDNA probe and breakpoint mapping","pmids":["1303177"],"confidence":"Medium","gaps":["Did not identify the recombining partner sequence","Breakpoints not sequenced at nucleotide resolution"]},{"year":1995,"claim":"Identification of the IDSP1/IDS-2 pseudogene and recombination junctions explained the structural instability as non-allelic homologous recombination, accounting for a recurrent (~13%) cause of Hunter syndrome and a confound for genomic diagnostics.","evidence":"Southern blot and junction sequencing of inversion alleles; mapping of homologous pseudogene sequences on Xq28","pmids":["7633410","8528670"],"confidence":"High","gaps":["Frequency estimates depend on cohort and detection method","Mechanism of inversion formation not reconstituted experimentally"]},{"year":1996,"claim":"Sequencing of an intragenic exon IV–VII deletion junction confirmed that gene-pseudogene exchange produces not only inversions but also deletions, extending the homologous-recombination model to multiple rearrangement classes.","evidence":"Southern blot, PCR, and breakpoint sequencing in two patients","pmids":["8807335"],"confidence":"Medium","gaps":["Based on two patients","Recombination not experimentally reconstituted"]},{"year":1997,"claim":"Discovery of a recurrent heptamer at deletion junctions showed that, alongside homologous recombination, illegitimate recombination at short direct repeats contributes to IDS rearrangements.","evidence":"Southern blot, PCR, and junction sequencing of two deletions 30 kb apart","pmids":["9244428"],"confidence":"Medium","gaps":["Single case study","Hotspot role of heptamer not proven mechanistically"]},{"year":1997,"claim":"Characterizing IDS biosynthesis defined the precursor-to-mature processing pathway and showed that intercellular enzyme transfer occurs chiefly by cell-to-cell contact rather than secretion, framing how cross-correction operates.","evidence":"Western blotting of processing in multiple cell lines plus coculture versus conditioned-medium transfer assays","pmids":["9024795"],"confidence":"Medium","gaps":["Molecular basis of contact-dependent transfer not defined","Processing protease(s) not identified"]},{"year":1995,"claim":"Identification of an alternative transcript lacking the C-terminal domain raised the possibility of an additional IDS protein form.","evidence":"cDNA cloning and sequencing of a 1.4-kb alternative transcript","pmids":["8530090"],"confidence":"Medium","gaps":["Functional significance of the truncated form not established","Protein product not detected in vivo"]},{"year":2006,"claim":"Systematic transcript analyses established that point and silent mutations frequently act by activating cryptic splice sites and that aberrant transcripts are subject to NMD, making splicing a dominant pathogenic mechanism distinct from coding changes.","evidence":"RT-PCR transcript cloning, real-time RT-PCR quantification, and cDNA/gDNA comparison across patient cohorts","pmids":["16699754","17063374","16495038"],"confidence":"Medium","gaps":["Variable NMD susceptibility across alleles not fully explained","Splice factor mechanisms not defined in these studies"]},{"year":2009,"claim":"Systemic AAV delivery showed that circulating IDS crosses the blood-brain barrier to correct CNS glycosaminoglycan storage, establishing the therapeutic principle that peripheral enzyme can treat CNS disease.","evidence":"Systemic AAV2/5-hIDS in MPSII mouse pups with long-term biochemical/histological assessment distinguishing brain transduction from circulating enzyme","pmids":["19679226"],"confidence":"High","gaps":["Molecular route of BBB crossing not identified","Mouse-to-human translation not addressed"]},{"year":2010,"claim":"Detection of wild-type IDS mRNA and protein in patients carrying only mutant genomic alleles raised the possibility of in vivo RNA-level correction of pathogenic mutations.","evidence":"Multiple orthogonal methods (pyrosequencing, SNuPE, real-time PCR, Western blot) with segregation analysis in three patients","pmids":["20104590"],"confidence":"Medium","gaps":["Proposed RNA editing mechanism not directly proven","Limited to three patients"]},{"year":2019,"claim":"Integrating structural modeling with expression assays linked specific missense substitutions to helix deformation, impaired maturation, and loss of activity, and connected genotype severity to residual activity and CNS involvement.","evidence":"Homology modeling, enzyme activity assays, and immunoblotting of intracellular processing for numerous variants across cohorts","pmids":["27246110","28543354","30639582","31877959"],"confidence":"Medium","gaps":["No experimental crystal structure","Quantitative activity thresholds protecting the CNS not precisely defined"]},{"year":2019,"claim":"Brain-targeted nanoparticle delivery of IDS restored enzyme activity and reduced storage and neuroinflammation in patient cells and MPSII mice, advancing CNS-directed enzyme replacement strategies.","evidence":"In vitro activity assays in patient fibroblasts and in vivo biochemical/histological assessment with g7-PLGA nanoparticles","pmids":["31022913"],"confidence":"Medium","gaps":["Single lab","Durability and human translation not established"]},{"year":2015,"claim":"Splicing-factor and antisense experiments began to define the cis- and trans-acting regulation of IDS exon 3 and exon 8 splice sites relevant to therapeutic splice modulation.","evidence":"Minigene splicing assays, SRSF2/hnRNP E1 overexpression, and antisense oligonucleotide transfection in fibroblasts","pmids":["26407519"],"confidence":"Medium","gaps":["Splice factor roles described as tentative","Antisense oligonucleotides generated additional aberrant products rather than correction"]},{"year":null,"claim":"The catalytic mechanism and high-resolution structure of human IDS, and the molecular basis of contact-dependent intercellular enzyme transfer, remain undefined in this corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimentally determined IDS structure in the timeline","Mechanism of cell-to-cell IDS transfer unresolved","Sulfatase catalytic chemistry not directly characterized here"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,15,16,17,20]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[11,18]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,16,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,9,16]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22304","full_name":"Iduronate 2-sulfatase","aliases":["Alpha-L-iduronate sulfate sulfatase","Idursulfase"],"length_aa":550,"mass_kda":61.9,"function":"Lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate","subcellular_location":"Lysosome","url":"https://www.uniprot.org/uniprotkb/P22304/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IDS","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IDS","total_profiled":1310},"omim":[{"mim_id":"620142","title":"CENTROSOMAL AT-AC SPLICING FACTOR; CENATAC","url":"https://www.omim.org/entry/620142"},{"mim_id":"619345","title":"DYSOSTOSIS MULTIPLEX, AIN-NAZ TYPE; DMAN","url":"https://www.omim.org/entry/619345"},{"mim_id":"608562","title":"POLYDACTYLY, POSTAXIAL, TYPE A4","url":"https://www.omim.org/entry/608562"},{"mim_id":"607108","title":"PAIRED BOX GENE 6; PAX6","url":"https://www.omim.org/entry/607108"},{"mim_id":"311360","title":"PREMATURE OVARIAN FAILURE 1; POF1","url":"https://www.omim.org/entry/311360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":432.1}],"url":"https://www.proteinatlas.org/search/IDS"},"hgnc":{"alias_symbol":["ID2S"],"prev_symbol":["SIDS"]},"alphafold":{"accession":"P22304","domains":[{"cath_id":"3.40.720.10","chopping":"39-164_189-267_286-456","consensus_level":"high","plddt":96.1073,"start":39,"end":456}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22304","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22304-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22304-F1-predicted_aligned_error_v6.png","plddt_mean":93.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IDS","jax_strain_url":"https://www.jax.org/strain/search?query=IDS"},"sequence":{"accession":"P22304","fasta_url":"https://rest.uniprot.org/uniprotkb/P22304.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22304/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22304"}},"corpus_meta":[{"pmid":"33038326","id":"PMC_33038326","title":"A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II.","date":"2020","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33038326","citation_count":140,"is_preprint":false},{"pmid":"7633410","id":"PMC_7633410","title":"Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome.","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7633410","citation_count":131,"is_preprint":false},{"pmid":"17556193","id":"PMC_17556193","title":"A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.","date":"2007","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/17556193","citation_count":122,"is_preprint":false},{"pmid":"11117528","id":"PMC_11117528","title":"The nuclear receptor corepressor (N-CoR) contains three isoleucine motifs (I/LXXII) that serve as receptor interaction domains (IDs).","date":"2000","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11117528","citation_count":122,"is_preprint":false},{"pmid":"17432962","id":"PMC_17432962","title":"Spinal cord injury-induced immune depression syndrome (SCI-IDS).","date":"2007","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17432962","citation_count":109,"is_preprint":false},{"pmid":"17214880","id":"PMC_17214880","title":"IDconverter and IDClight: conversion and annotation of gene and protein IDs.","date":"2007","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/17214880","citation_count":101,"is_preprint":false},{"pmid":"16407553","id":"PMC_16407553","title":"Inhibitors of differentiation and DNA binding (Ids) regulate Math1 and hair cell formation during the development of the organ of Corti.","date":"2006","source":"The Journal 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V. 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(SIDS).","date":"2024","source":"International journal of legal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38849547","citation_count":9,"is_preprint":false},{"pmid":"21910981","id":"PMC_21910981","title":"A novel mutation of IDS gene in a Chinese patient with mucopolysaccharidosis II by next-generation sequencing.","date":"2011","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21910981","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49543,"output_tokens":5026,"usd":0.112009,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13428,"output_tokens":3896,"usd":0.08227,"stage2_stop_reason":"end_turn"},"total_usd":0.194279,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The IDS gene encoding iduronate-2-sulfatase spans approximately 24 kb and is split into nine exons. The promoter lacks a TATA box but contains GC box consensus sequences, consistent with housekeeping gene regulation.\",\n      \"method\": \"Genomic cloning and sequencing of overlapping genomic clones; promoter region analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing of the entire gene structure from overlapping genomic clones, foundational structural characterization replicated in subsequent studies\",\n      \"pmids\": [\"8244397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Inversion of the IDS gene resulting from recombination between homologous sequences in intron 7 of IDS and sequences near exon 3 of the IDS-related locus (IDS-2/IDSP1), located within 90 kb telomeric of IDS, is a common cause (~13%) of Hunter syndrome. No deletions or insertions accompany the recombination.\",\n      \"method\": \"Southern blot analysis and nucleotide sequencing of rearrangement junctions in Hunter syndrome patients\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing of recombination junctions in multiple patients, replicated across multiple studies\",\n      \"pmids\": [\"7633410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"An IDS-related locus (IDS-2/IDSP1) exists within 80 kb telomeric of the functional IDS gene on Xq28, containing sequences homologous to exons 2 and 3 and introns 2, 3, and 7 of IDS (exon 3 sequences show 100% identity). This locus complicates mutational analysis of genomic DNA from Hunter syndrome patients.\",\n      \"method\": \"Southern blot analysis, PCR amplification, and sequencing to map homologous sequences\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct sequencing and Southern blot characterization, independently confirmed in multiple subsequent studies\",\n      \"pmids\": [\"8528670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Structural alterations (large deletions and major rearrangements) in the IDS gene were found in ~20% of MPS-II patients. A region within IDS is prone to structural alterations, with six of seven rearrangements showing similar or identical Southern blot patterns, suggesting a recombination hotspot.\",\n      \"method\": \"Southern blot analysis of 46 unrelated MPS-II patients using a full-length IDS cDNA probe; deletion breakpoint mapping with flanking markers\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Southern blot with multiple patients, single lab, two orthogonal approaches (hybridization + flanking markers)\",\n      \"pmids\": [\"1303177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"An alternative 1.4-kb IDS transcript was identified that encodes a protein identical to full-length IDS except for the absence of the 207-amino-acid C-terminal domain, which is replaced by 7 amino acids, suggesting possible existence of an additional IDS enzyme form.\",\n      \"method\": \"cDNA cloning and sequencing of alternative transcript\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, cDNA cloning and sequencing; functional significance not established\",\n      \"pmids\": [\"8530090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"IDS is processed from two precursor forms (76 and 90 kDa) through a series of intermediate forms to mature 55- and 45-kDa polypeptides in fibroblasts, COS cells, and lymphoblastoid cell lines. Transfer of IDS from overexpressing cells to IDS-deficient cells occurs preferentially by cell-to-cell contact rather than through secreted enzyme, as IDS precursors are poorly secreted. The 76- and 62-kDa transferred IDS polypeptides are correctly processed to the mature 55- and 45-kDa forms in recipient fibroblasts.\",\n      \"method\": \"Western blotting of IDS processing in multiple cell lines; coculture and conditioned medium transfer experiments with transfected cells and IDS-deficient fibroblasts\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization of processing steps and transfer mechanism using multiple cell lines and orthogonal experimental approaches (coculture vs. conditioned medium)\",\n      \"pmids\": [\"9024795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"An intragenic IDS deletion (removing exons IV–VII) results from gene-pseudogene exchange between highly homologous regions in intron 3 and intron 7 of IDS and the IDS-2 pseudogene, producing a rearranged gene with junction intron containing pseudogene intron 3- and intron 7-related sequences.\",\n      \"method\": \"Southern blot and PCR characterization of deletion junctions; sequencing of breakpoint regions\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct sequencing of recombination junctions, single lab, two patients\",\n      \"pmids\": [\"8807335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Two distinct deletions in the IDS gene region, separated by 30 kb, result from non-homologous (illegitimate) recombination events between short direct repeats. The heptamer sequence 5'-TACTCTA-3' is present at both deletion junctions, suggesting it is a recombination hotspot.\",\n      \"method\": \"Southern blot, PCR, and nucleotide sequencing of deletion junctions\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct sequencing confirming recombination mechanism at both junctions, single case study\",\n      \"pmids\": [\"9244428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Point mutations in the IDS gene can activate multiple cryptic splice sites. Mutations at invariant splice-site motifs (c.418+1G>C) produce only aberrantly spliced transcripts, while mutations in variant motifs (c.419G>T) or coding regions (c.245C>T) lead to a mixture of aberrant and correctly spliced transcripts. Nonsense-mediated mRNA decay (NMD) reduces mRNA levels for some aberrant transcripts.\",\n      \"method\": \"RT-PCR cloning and sequencing of transcripts; real-time RT-PCR quantification of mRNA levels; computational analysis of splice site scores\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RT-PCR characterization of aberrant transcripts combined with quantitative real-time PCR, multiple patients studied\",\n      \"pmids\": [\"16699754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Splice mutations in the IDS gene account for ~56% of MPS II cases in a Portuguese cohort. Mutations affecting the splicing of exon 3 are particularly common, and some mutations cause dramatic changes in splicing mechanism including revelation of a cryptic exonic sequence inside intron 3. cDNA analysis is required alongside gDNA analysis to correctly classify IDS mutations.\",\n      \"method\": \"Genomic DNA sequencing and cDNA analysis by RT-PCR in 16 unrelated MPS II patients\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal gDNA and cDNA analyses in a cohort of patients establishing splicing mechanism\",\n      \"pmids\": [\"17063374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nonsense and nonstop mutations in IDS lead to reduced mRNA levels via nonsense-mediated decay (NMD) and nonstop mRNA decay pathways, respectively, as measured by real-time RT-PCR. Two mutations (Q66X and V136fs75X) produced transcripts evading mRNA surveillance despite fulfilling the known criteria, showing variability in NMD susceptibility at the IDS locus.\",\n      \"method\": \"Real-time RT-PCR quantification of IDS mRNA levels; characterization of 17 patient alleles\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative real-time RT-PCR used systematically across multiple alleles to assess mRNA decay pathways\",\n      \"pmids\": [\"16495038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Systemic AAV-mediated delivery of hIDS in MPSII mice results in high circulating IDS levels that cross the blood-brain barrier and correct CNS glycosaminoglycan accumulation and CNS defects. The CNS correction arises from the enzyme crossing the BBB, not from brain transduction.\",\n      \"method\": \"Systemic injection of AAV2/5CMV-hIDS in MPSII mouse pups; biochemical and histological assessment of visceral organs and brain at up to 18 months post-treatment\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with long-term follow-up, biochemical and histological outcomes, BBB crossing established by comparing brain transduction vs. circulating enzyme\",\n      \"pmids\": [\"19679226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The synonymous IDS mutation c.879G>A (p.Gln293Gln) activates a cryptic splice site, causing a 28-bp deletion and premature termination at p.Tyr285GlufsX47, demonstrating that silent variants can cause pathogenic splicing alterations in the IDS gene.\",\n      \"method\": \"RT-PCR and Sanger sequencing of cDNA from patient fibroblasts; X-inactivation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RT-PCR and sequencing directly demonstrating aberrant splicing at RNA level, complemented by X-inactivation analysis\",\n      \"pmids\": [\"21829674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Complex rearrangements at the IDS locus initiated by non-allelic homologous recombination between IDS and the nearby pseudogene IDSP1 (a low-copy repeat) can be resolved either by Alu-mediated recombination or by non-homologous end joining, producing partial deletion plus inverted insertion configurations.\",\n      \"method\": \"Southern blot, PCR, and in silico analysis of repetitive elements at rearrangement junctions in two MPS II patients\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct sequencing and in silico analysis of two cases, mechanistic model proposed but not experimentally reconstituted\",\n      \"pmids\": [\"21593745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRSF2 and hnRNP E1 may be involved respectively in activation and repression of the constitutive 3' splice site of IDS exon 3 (established by minigene and overexpression assays for mutations c.241C>T and c.257C>T). Antisense morpholino oligonucleotides and locked nucleic acids targeting the c.1122C>T aberrant splice site in exon 8 failed to abolish the abnormal transcript and instead generated additional aberrant splicing products, indicating that the oligonucleotides masked a cis-acting element required for normal 5' splice site regulation.\",\n      \"method\": \"Cell-based splicing assays with mutant minigenes; overexpression assays; transfection of antisense oligonucleotides in patient and control fibroblasts\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene and overexpression assays in cell lines, antisense oligonucleotide experiments in patient fibroblasts; single lab\",\n      \"pmids\": [\"26407519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homology modeling of IDS missense variants predicts that the P120R substitution (severe MPS II) deforms an α-helix (I119–F123), causing major structural alteration, whereas N534I (attenuated MPS II) has marginal structural effect. Expression studies of nine IDS variants showed impaired enzymatic activity and aberrant intracellular processing (by immunoblotting) irrespective of phenotype.\",\n      \"method\": \"Homology modeling of IDS structure; expression studies with immunoblotting for intracellular processing; IDS enzyme activity assays in patient-derived cells\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical activity and processing assays combined with structural modeling; single lab\",\n      \"pmids\": [\"27246110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Expression studies of IDS variants demonstrated impaired enzymatic activity and aberrant intracellular processing; total deletion of IDS invariably results in neuronopathic MPS II phenotype. Low or cell-type-specific residual IDS activity may be sufficient to prevent the neuronal phenotype.\",\n      \"method\": \"IDS enzyme activity assays; immunoblotting for IDS protein processing; quantification of urinary glycosaminoglycans by mass spectrometry in a cohort of Dutch MPS II patients\",\n      \"journal\": \"Developmental medicine and child neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity and immunoblotting in a defined cohort; single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"28543354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In vitro expression studies of novel IDS missense mutations showed significantly decreased IDS enzymatic activity. Western blotting demonstrated that examined mutations produce IDS precursor protein at similar or slightly lower molecular mass without detectable mature forms, indicating impaired post-translational processing.\",\n      \"method\": \"Transient expression studies; IDS enzyme activity assay; Western blotting of transfected cells\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays with enzyme activity and Western blotting; single lab\",\n      \"pmids\": [\"30639582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IDS-loaded brain-targeted PLGA nanoparticles (g7-NPs) deliver functional IDS enzyme to fibroblasts from MPS II patients, restoring IDS activity to levels comparable to healthy cells and reducing GAG content to non-pathological levels. In MPSII mice, weekly g7-NPs-IDS administration reduced GAG deposits and neuroinflammatory markers in both liver and brain tissues.\",\n      \"method\": \"In vitro IDS activity assay in patient fibroblasts; in vivo biochemical, histological, and immunohistochemical assessment in MPSII mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with direct biochemical and histological readouts; single lab\",\n      \"pmids\": [\"31022913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wild-type IDS mRNA transcripts were detected in the cDNA of three Hunter syndrome patients carrying IDS nonsense or frameshift mutations in genomic DNA, with no wild-type IDS genomic sequence detectable. Multiple methods (restriction enzyme digestion, clone sequencing, pyrosequencing, SNuPE, real-time PCR, Western blotting) confirmed both the mutant genomic sequence and the presence of some wild-type IDS protein, suggesting possible in vivo RNA-level correction of the mutations.\",\n      \"method\": \"Restriction enzyme digestion, clone sequencing, pyrosequencing, SNuPE, real-time PCR, Western blotting; segregation analysis of linked IDS polymorphism to exclude maternal X-chromosome contamination\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods confirming the finding in three patients; proposed mechanism (RNA editing) not directly proven\",\n      \"pmids\": [\"20104590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In vitro expression studies of novel IDS missense mutations (c.137A>C, c.311A>T, c.454A>C, c.797C>G, c.817C>T, c.998C>T, c.1106C>G, c.1400C>T, c.1402C>T, c.1403G>A) showed significantly decreased IDS enzymatic activity, establishing their pathogenic nature.\",\n      \"method\": \"In vitro IDS activity assay in transiently transfected cells expressing novel IDS variants\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro enzyme activity assays across multiple novel variants; single lab\",\n      \"pmids\": [\"31877959\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDS (iduronate-2-sulfatase) is a lysosomal enzyme encoded by a 9-exon, ~24-kb X-linked gene (Xq28) that degrades heparan sulfate and dermatan sulfate; it is synthesized as 76–90 kDa precursor forms that are processed through intermediate forms to mature 55- and 45-kDa polypeptides, with transfer between cells occurring preferentially by cell-to-cell contact; ~13–20% of MPS II mutations arise from recombination-driven inversions or deletions between IDS and the nearby pseudogene IDSP1 at established hotspots (intron 7/exon 3 region), while point mutations frequently cause aberrant splicing by activating cryptic splice sites, and some nonsense/frameshift alleles undergo nonsense-mediated mRNA decay; circulating IDS enzyme can cross the blood-brain barrier to correct CNS glycosaminoglycan accumulation in mouse models, a property exploited therapeutically.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IDS encodes iduronate-2-sulfatase, a lysosomal sulfatase whose deficiency causes the X-linked lysosomal storage disorder mucopolysaccharidosis type II (Hunter syndrome) [#11, #16]. The gene spans ~24 kb across nine exons and is driven by a TATA-less, GC-box-containing promoter characteristic of housekeeping genes [#0]. The enzyme is synthesized as 76- and 90-kDa precursors that are post-translationally processed through intermediate forms to mature 55- and 45-kDa polypeptides; because precursors are poorly secreted, IDS transfers to enzyme-deficient cells preferentially by cell-to-cell contact, after which the transferred polypeptides are correctly matured in recipient cells [#5]. Pathogenic missense variants typically retain only precursor protein with impaired or absent maturation and reduced catalytic activity, and total loss of IDS produces the neuronopathic phenotype while low residual activity can spare the CNS [#16, #17, #20]. A major share of disease-causing alleles arise from genomic rearrangement: non-allelic homologous recombination between IDS and the adjacent IDSP1 (IDS-2) pseudogene ~80\\u201390 kb telomeric on Xq28\\u2014whose exon 3 sequence is 100% identical to IDS\\u2014drives recurrent inversions and intragenic deletions at intron 7/exon 3 hotspots [#1, #2, #6], while additional rearrangements occur through illegitimate recombination at short direct-repeat hotspots [#7, #13]. A second large class of mutations, including synonymous variants, disrupts splicing by activating cryptic splice sites and engaging nonsense-mediated and nonstop mRNA decay [#8, #9, #12]. The capacity of circulating IDS to cross the blood-brain barrier and correct CNS glycosaminoglycan accumulation has been exploited therapeutically in mouse models [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the genomic architecture and promoter character of IDS defined the gene as a constitutively expressed locus and provided the structural framework for all subsequent mutation analysis.\",\n      \"evidence\": \"Genomic cloning, sequencing of nine exons, and promoter analysis\",\n      \"pmids\": [\"8244397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address protein structure or catalytic mechanism\", \"No functional confirmation of housekeeping expression in vivo\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Detection of large deletions and rearrangements in ~20% of MPS II patients revealed that a region of IDS is structurally unstable, pointing to a recombination hotspot before its mechanism was known.\",\n      \"evidence\": \"Southern blot of 46 unrelated MPS-II patients with full-length cDNA probe and breakpoint mapping\",\n      \"pmids\": [\"1303177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the recombining partner sequence\", \"Breakpoints not sequenced at nucleotide resolution\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of the IDSP1/IDS-2 pseudogene and recombination junctions explained the structural instability as non-allelic homologous recombination, accounting for a recurrent (~13%) cause of Hunter syndrome and a confound for genomic diagnostics.\",\n      \"evidence\": \"Southern blot and junction sequencing of inversion alleles; mapping of homologous pseudogene sequences on Xq28\",\n      \"pmids\": [\"7633410\", \"8528670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency estimates depend on cohort and detection method\", \"Mechanism of inversion formation not reconstituted experimentally\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Sequencing of an intragenic exon IV\\u2013VII deletion junction confirmed that gene-pseudogene exchange produces not only inversions but also deletions, extending the homologous-recombination model to multiple rearrangement classes.\",\n      \"evidence\": \"Southern blot, PCR, and breakpoint sequencing in two patients\",\n      \"pmids\": [\"8807335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on two patients\", \"Recombination not experimentally reconstituted\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery of a recurrent heptamer at deletion junctions showed that, alongside homologous recombination, illegitimate recombination at short direct repeats contributes to IDS rearrangements.\",\n      \"evidence\": \"Southern blot, PCR, and junction sequencing of two deletions 30 kb apart\",\n      \"pmids\": [\"9244428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case study\", \"Hotspot role of heptamer not proven mechanistically\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Characterizing IDS biosynthesis defined the precursor-to-mature processing pathway and showed that intercellular enzyme transfer occurs chiefly by cell-to-cell contact rather than secretion, framing how cross-correction operates.\",\n      \"evidence\": \"Western blotting of processing in multiple cell lines plus coculture versus conditioned-medium transfer assays\",\n      \"pmids\": [\"9024795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of contact-dependent transfer not defined\", \"Processing protease(s) not identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of an alternative transcript lacking the C-terminal domain raised the possibility of an additional IDS protein form.\",\n      \"evidence\": \"cDNA cloning and sequencing of a 1.4-kb alternative transcript\",\n      \"pmids\": [\"8530090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of the truncated form not established\", \"Protein product not detected in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Systematic transcript analyses established that point and silent mutations frequently act by activating cryptic splice sites and that aberrant transcripts are subject to NMD, making splicing a dominant pathogenic mechanism distinct from coding changes.\",\n      \"evidence\": \"RT-PCR transcript cloning, real-time RT-PCR quantification, and cDNA/gDNA comparison across patient cohorts\",\n      \"pmids\": [\"16699754\", \"17063374\", \"16495038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Variable NMD susceptibility across alleles not fully explained\", \"Splice factor mechanisms not defined in these studies\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Systemic AAV delivery showed that circulating IDS crosses the blood-brain barrier to correct CNS glycosaminoglycan storage, establishing the therapeutic principle that peripheral enzyme can treat CNS disease.\",\n      \"evidence\": \"Systemic AAV2/5-hIDS in MPSII mouse pups with long-term biochemical/histological assessment distinguishing brain transduction from circulating enzyme\",\n      \"pmids\": [\"19679226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular route of BBB crossing not identified\", \"Mouse-to-human translation not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Detection of wild-type IDS mRNA and protein in patients carrying only mutant genomic alleles raised the possibility of in vivo RNA-level correction of pathogenic mutations.\",\n      \"evidence\": \"Multiple orthogonal methods (pyrosequencing, SNuPE, real-time PCR, Western blot) with segregation analysis in three patients\",\n      \"pmids\": [\"20104590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed RNA editing mechanism not directly proven\", \"Limited to three patients\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Integrating structural modeling with expression assays linked specific missense substitutions to helix deformation, impaired maturation, and loss of activity, and connected genotype severity to residual activity and CNS involvement.\",\n      \"evidence\": \"Homology modeling, enzyme activity assays, and immunoblotting of intracellular processing for numerous variants across cohorts\",\n      \"pmids\": [\"27246110\", \"28543354\", \"30639582\", \"31877959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental crystal structure\", \"Quantitative activity thresholds protecting the CNS not precisely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Brain-targeted nanoparticle delivery of IDS restored enzyme activity and reduced storage and neuroinflammation in patient cells and MPSII mice, advancing CNS-directed enzyme replacement strategies.\",\n      \"evidence\": \"In vitro activity assays in patient fibroblasts and in vivo biochemical/histological assessment with g7-PLGA nanoparticles\",\n      \"pmids\": [\"31022913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Durability and human translation not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Splicing-factor and antisense experiments began to define the cis- and trans-acting regulation of IDS exon 3 and exon 8 splice sites relevant to therapeutic splice modulation.\",\n      \"evidence\": \"Minigene splicing assays, SRSF2/hnRNP E1 overexpression, and antisense oligonucleotide transfection in fibroblasts\",\n      \"pmids\": [\"26407519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splice factor roles described as tentative\", \"Antisense oligonucleotides generated additional aberrant products rather than correction\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic mechanism and high-resolution structure of human IDS, and the molecular basis of contact-dependent intercellular enzyme transfer, remain undefined in this corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimentally determined IDS structure in the timeline\", \"Mechanism of cell-to-cell IDS transfer unresolved\", \"Sulfatase catalytic chemistry not directly characterized here\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 15, 16, 17, 20]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 16, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 9, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}