GALNS

Summary: The source-specific 4-sulfatase claim remains unresolved.

Reason: GO:0003943 specifies GalNAc 4-desulfation, whereas the accessible human GALNS primary study PMID:22940367 explicitly identifies 6-sulfated galactosides and directly measures synthetic 4-MU-Gal6S hydrolysis. This is positive evidence for the normal 6S specificity; it is not a matched assay establishing that every 4S reaction is absent. The authentic PMID:8325655 abstract mentions a fibroblast enzyme assay, but its exact substrate and complete Methods remain inaccessible. Correcting the separate ARSB contribution in PMID:820716 and the selected diagnostic studies PMID:1522213 and PMID:24726177 do not supply the missing comparison. A lateral MODIFY could correct a demonstrated positional mapping error even though GO:0043890 is not a descendant of GO:0003943. Here the specific original assertion is unresolved, so retain UNDECIDED without an invented proven source defect. Synthetic aryl-sulfate turnover does not settle sugar 4-desulfation.

Summary: Human GALNS has measured synthetic arylsulfatase activity outside its defining glycan-substrate role.

Reason: Purified recombinant human GALNS directly hydrolyzes 4-methylumbelliferyl sulfate in PMID:22940367, which matches the official phenol-sulfate hydrolysis definition of GO:0004065. The measured kcat is 4.2/min, with substrate inhibition, compared with 228/min for the coupled 4-MU-Gal6S assay. This supports the chemistry without making an aryl substrate a demonstrated physiological target. The actual PTHR42693 tree and alignment place the exact 522-residue human target beneath the PTN000819263 IBD node, with no intervening negative assertion. The authors explicitly describe substantial substrate-recognition promiscuity. Retain the IBA as a non-core catalytic capability demonstrated on a synthetic substrate, with no wrong-family or propagation error. The older incoming five-donor list and later six-donor IBD remain separate dated records. KEEP_AS_NON_CORE retains directly measured turnover of the substrate class actually defined by this molecular-function term; it does not promote the synthetic assay to a physiological role or a core function.

Summary: GALNS is represented among cargo released from azurophil granules.

Reason: The official R-HSA-6798751 event releases azurophil granule lumen proteins, and its output set R-HSA-6806184 explicitly contains OxA-GALNS. This supports modeled extracellular occurrence after secretion. It does not establish a physiological extracellular GALNS substrate or make GALNS an executor of the exocytosis mechanism. The lysosomal glycan-desulfation role remains defining. The named participant chain was read; individual component-page requests returned 404, so no independently resolved component-to-accession response is claimed.

Summary: Direct human fibroblast immunolocalization places GALNS in lysosomes.

Reason: PMID:30760748 reports GALNS/LAMP1 colocalization in fixed, permeabilized primary human central-airway fibroblasts from ever smokers and COPD patients. The localization Results and Figure 4 caption describe both groups, with at least three individuals per group. This directly supports the lysosome annotation without requiring exclusive localization or a disease-specific molecular function. The figure images and supplemental antibody table were not independently inspected; no additional reagent or isoform detail is invented.

Summary: The electronic lysosome location agrees with direct human GALNS localization.

Reason: GALNS is a lysosomal glycan sulfatase, and PMID:30760748 directly colocalizes GALNS with LAMP1 in cultured primary human airway fibroblasts from both ever smokers and COPD subjects. The electronic ARBA, ortholog and UniProt location identifiers are preserved, with independent target evidence supporting the compartment. Lysosome remains an informative accepted organelle location alongside the more precise lysosomal-lumen statements; no exclusive residence or new COPD process role is inferred.

Summary: The directly measured sulfatase activity can be expressed by the specific GALNS 6-sulfatase term.

Reason: PMID:15962010 actually assays GALNS cDNA in transfected Cos7 cells: Figure 4 shows GALNS activity and its enhancement by SUMF1. The broad sulfuric ester hydrolase annotation is therefore supported. The inaccessible supplement contains detailed enzyme protocols, so its exact GALNS assay substrate is not asserted. Independent human GALNS enzymology and the established natural glycan reaction support GO:0043890, an officially verified is_a child of GO:0008484, as the more informative molecular function. This refinement does not assign GALNS a role in modifying other sulfatases.

Proposed replacements: N-acetylgalactosamine-6-sulfatase activity

Summary: GALNS catalyzes a desulfation step in chondroitin sulfate proteoglycan breakdown.

Reason: GALNS performs the hydrolytic step in chondroitin sulfate catabolism. The PMID:18285341 abstract collectively describes ASB-or-GALNS manipulation and CS/C4S outcomes. The selected original GALNS-specific Results, Table 2 and Figure 2 caption instead report changed total CS without a C4S increase after GALNS silencing or a C4S change after overexpression; these are the per-gene results used here. Table 1 separately measures enzyme activity and shows the GALNS manipulation with essentially unchanged ASB activity. This supports a chondroitin-catabolic role but is not a purified 4S-versus-6S comparison or proof of universal absence of a 4S side reaction. PMID:820716 independently measures desulfation of chondroitin-6-sulfate oligosaccharides. Intact-polymer cleavage and direct signaling are not inferred.

Summary: GALNS occurs in the modeled azurophil granule lumen cargo set.

Reason: The successful official participant page for R-HSA-6798742, the lumen-protein input of R-HSA-6798751, explicitly lists OxA-GALNS. Retain this specialized secretory-granule location as context, not a second defining function. The event models release of pre-existing cargo and does not show GALNS catalyzing granule formation or fusion. The named set membership is positive evidence even though the individual component endpoint was inaccessible; no extra experiment or resolved accession join is claimed.

Summary: The normal GALNS keratan-desulfation reaction occurs in lysosomal lumen.

Reason: The retained normal Reactome R-HSA-1630304 record describes GALNS oligomer removing sulfate from Gal6S in keratan sulfate and explicitly assigns lysosomal lumen. That location coheres with the enzyme substrate pathway and direct human lysosomal immunolocalization in PMID:30760748. The selected official event record was read, while its downstream individual catalyst component was not independently resolved; the conclusion does not require pretending an inaccessible component page was inspected.

Summary: The disease model preserves the normal lysosomal-lumen context of GALNS.

Reason: Reactome R-HSA-2263490 places the defective GALNS reaction in lysosomal lumen and connects it to the normal R-HSA-1630304 reaction. The normal gene product is a lysosomal enzyme, supported independently by human localization and catalytic evidence. Retain the location without inferring that every disease variant is correctly trafficked or active: the disease-event context is not a variant-by-variant localization assay.

Summary: Purified human GALNS catalyzes the 6-desulfation reaction represented by GO:0043890.

Reason: PMID:22940367 expresses human GALNS with its native signal sequence and a purification His tag in insect cells, and directly measures hydrolysis of 4-MU-Gal6S in a coupled assay with beta-galactosidase. Controls lacking either enzyme remain at background. The structure and mass spectrometry support maturation of Cys79 to the catalytic formylglycine and the calcium-containing active site. The physiological substrate scope is supported by the established glycan pathway and prior human biochemical work, rather than pretending the synthetic substrate is an intact native polymer. The product-soaked GalNAc pose is nonproductive and is not a resolved sulfated-substrate orientation.

Summary: Human GALNS manipulation supports its 6-sulfatase activity in a chondroitin-catabolic context.

Reason: Selected original PMID:18285341 Methods and Table 1 identify human GALNS NM_000512 expressed or silenced in MCF-7 cells. GALNS activity decreases with its siRNA and increases with overexpression, while ASB activity is essentially unchanged. The detailed GALNS assay recipe refers to earlier papers; the explicit 4-MU-sulfate recipe in this article is for ASB. Retain the source-specific 6-sulfatase assertion and its literal part_of GO:0030207 extension, corroborated by purified human GALNS kinetics. The distinct CS/C4S outcome is interpreted with the original Results/Table 2/Figure 2 scope in the process annotation; this cellular readout does not establish universal substrate exclusion.

Summary: The electronic 6-sulfatase annotation matches the established human enzyme chemistry.

Reason: GO:0043890 includes hydrolysis of both GalNAc 6-sulfate in chondroitin sulfate and galactose 6-sulfate in keratan sulfate. Human kidney oligosaccharide assays in PMID:820716 and recombinant human GALNS studies in PMID:22940367 independently support this catalytic identity. The literal ARBA, ortholog, InterPro and EC source identifiers remain unchanged; their presence is not treated as a substitute for the target evidence or as proof that every donor experiment was inspected. One molecular-function term covers both natural sugar classes.

Summary: The disease reaction is consistent with the normal GALNS 6-sulfatase function.

Reason: Reactome R-HSA-2263490 describes defective GALNS variants that fail to hydrolyze Gal6S in keratan sulfate. Its loss-of-function wording does not mean that wild-type GALNS lacks the activity. The entry links the normal GALNS oligomer reaction R-HSA-1630304 in lysosomal lumen, and independent human enzymology supports that normal reaction. Preserve the disease-event citation while distinguishing defective modeled participants from the normal gene-product activity. The official term includes the keratan galactose substrate despite its GalNAc-oriented label.

Summary: GALNS is detected in the isolated urinary fraction, but specific exosome association remains unresolved.

Reason: The complete original PMID:23533145 main text and authentic Supplemental Table 2 identify P34059/GALNS at row 319, with 7, 7, 10 and 9 unique peptides across pooled cancer/non-cancer duplicate analyses. Differential ultracentrifugation and washing followed by LC-MS establish positive detection in the isolated fraction. More peptide identifications do not distinguish vesicle incorporation, surface association or co-isolation of a secreted lysosomal enzyme. The recovered target table does not resolve the co-isolation concern recorded in the October 10 review. Restore MARK_AS_OVER_ANNOTATED for the specific extracellular-exosome location while preserving the positive fraction-associated observation; this is not an assertion that GALNS is absent from extracellular vesicles or that an inaccessible experiment was negative.

Summary: GALNS catalyzes keratan-chain desulfation during lysosomal proteoglycan degradation.

Reason: Retain this inherited proposal separately from the 15 current GOA contexts. GALNS itself hydrolyzes a Gal6S sulfate ester in the degradative pathway, as represented by the normal Reactome R-HSA-1630304 reaction and established substrate specificity discussed alongside direct human enzyme assays in PMID:22940367. This is catalytic participation, not mere necessity or substrate status. Human GLB1 and GNS provide same-role comparator annotations for GO:0042340; the comparator source paper was not independently re-read. Official typed ancestry shows that this keratan process is neither an ancestor nor a descendant of the existing chondroitin process GO:0030207. The complete retained GO-CAM index has no target hit, which is not treated as proof of a gap. The MCF-7 keratan-abundance result in PMID:18285341 is unchanged and is not used as a direct positive keratan assay. No redundant process ancestor or second molecular-function term is added. The pathway R-HSA-2022857 supplies proteoglycan-degradation context for the target-specific reaction. The repository module is concordant, but it cites this gene review and is not used as independent evidence.