Comparison of two phenotypically distinct lattice corneal dystrophies caused by mutations in the transforming growth factor beta induced (TGFBI) gene.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:24302499", "kind": "science-record", "revision": 2, "content_hash": "sha256:96c7c740f71f50777f5dda499741175ff556ea00a41925040e30716a789f8418", "created_at": "2026-11-01T15:40:03Z", "updated_at": "2026-11-01T18:46:58Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Comparison of two phenotypically distinct lattice corneal dystrophies caused by mutations in the transforming growth factor beta induced (TGFBI) gene.", "doi": "10.1002/prca.201300058", "pmid": "24302499", "authors": ["Ebbe Toftgaard Poulsen", "Kasper Runager", "Michael W Risør", "Thomas F Dyrlund", "Carsten Scavenius", "Henrik Karring", "Jeppe Praetorius", "Henrik Vorum", "Daniel E Otzen", "Gordon K Klintworth", "Jan J Enghild"], "journal": "Proteomics. Clinical applications", "year": 2014, "abstract": "PURPOSE: In this study, we investigated whether the phenotypic difference observed between two lattice corneal dystrophy type 1 (LCD type 1) cases caused by either a single A546D substitution or an A546D/P551Q double substitution in TGFBIp (transforming growth factor beta induced protein) can be ascribed to (i) a difference in the proteomes of corneal amyloid deposits, (ii) altered proteolysis of TGFBIp, or (iii) structural changes of TGFBIp introduced by the P551Q amino acid substitution.\nEXPERIMENTAL DESIGN: Amyloid deposits were isolated from the corneas of two siblings with LCD type 1 resulting from A546D/P551Q mutations in the TGFBI gene using laser capture microdissection and subsequently analyzed by LC-MS/MS. Proteolytic processing of TGFBIp was addressed by counting peptide spectra. Lastly, to study the possible effect of the P551Q substitution, recombinant FAS1-4 domain variants were subjected to in vitro stability assays.\nRESULTS: The amyloid proteomes and TGFBIp processing of the two A546D/P551Q LCD type 1 cases were similar to each other as well as to the A546D amyloid proteome previously reported by us. The stability assays revealed a minor destabilization of the FAS1-4 domain upon the addition of the P551Q mutation, moreover, it resulted in different accessibility to tryptic cleavage sites between the A546D and A546D/P551Q mutant FAS1-4 domain variants.\nCONCLUSION AND CLINICAL RELEVANCE: The difference in A546D and A546D/P551Q LCD type 1 phenotypes cannot be ascribed to altered corneal amyloid composition or altered in vivo proteolytic processing of TGFBIp. Instead, a small difference in thermodynamic stability introduced by the P551Q mutation most likely causes structural changes of TGFBIp. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000307 (http://proteomecentral.proteomexchange.org/dataset/PXD000307).", "claims": [{"id": "claim-target-result", "statement": "The study used decoy-database false-discovery-rate control (1.5–7% FDR, p < 0.01), Mascot searching, four technical replicates, and emPAI-based relative quantification of LC-MS/MS data; the underlying mass-spectrometry data were deposited in ProteomeXchange via PRIDE (PXD000307; DOI 10.6019/PXD000307). Headline result: the phenotypic difference between A546D and A546D/P551Q LCD type 1 cannot be explained by altered corneal amyloid composition or in vivo TGFBIp proteolysis and instead most likely reflects structural changes caused by the small stability effect of P551Q.", "kind": "quantitative", "target": {"value": 7.0, "unit": "per cent", "tolerance": null, "source": "All data sets were simultaneously searched against the decoy database to apply a false discovery rate (FDR) between 1.5 to 7% and a p-value < 0.01."}, "evidence": [{"asset": "source:pmid:24302499", "locator": "sections[8] \"2.4. Data handling\" paragraph 2", "quote": "All data sets were simultaneously searched against the decoy database to apply a false discovery rate (FDR) between 1.5 to 7% and a p-value < 0.01."}, {"asset": "source:pmid:24302499", "locator": "sections[8] \"2.4. Data handling\" paragraph 4", "quote": "For each sample, four technical replicates were run. Rough relative protein quantification was performed using the exponentially modified Protein Abundance Index (emPAI)."}, {"asset": "source:pmid:24302499", "locator": "sections[26] \"fn-group\" paragraph 1", "quote": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository [17] with the dataset identifier PXD000307 and DOI 10.6019/PXD000307."}, {"asset": "source:pmid:24302499", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "The difference in A546D and A546D/P551Q LCD type 1 phenotypes cannot be ascribed to altered corneal amyloid composition or altered in vivo proteolytic processing of TGFBIp. Instead, a small difference in thermodynamic stability introduced by the P551Q mutation most likely causes structural changes of TGFBIp."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The study used decoy-database false-discovery-rate control (1.5–7% FDR, p < 0.01), Mascot searching, four technical replicates, and emPAI-based relative quantification of LC-MS/MS data; the underlying mass-spectrometry data were deposited in ProteomeXchange via PRIDE (PXD000307; DOI 10.6019/PXD000307). Headline result: the phenotypic difference between A546D and A546D/P551Q LCD type 1 cannot be explained by altered corneal amyloid composition or in vivo TGFBIp proteolysis and instead most likely reflects structural changes caused by the small stability effect of P551Q.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:24302499"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:24302499", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1002/prca.201300058", "sha256": "sha256:9e7c63d9207f9612211c290f11054ed219c5c92e03a71ff61e2cc752472a486d", "bytes": 31971, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1002/prca.201300058", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC4163973", "source": "ncbi_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}], "gaps": []}, "analysis": {"state": "absent", "methods": [], "targets": [{"id": "target-published-estimate", "claim_id": "claim-target-result", "operation": null, "expected_value": 7.0, "unit": "per cent", "tolerance": null, "state": "complete", "note": "The published estimate as the reader quoted it from the paper. No tolerance is published because the paper states none."}, {"id": "target-published-estimate-p-value", "claim_id": "claim-target-result", "operation": null, "expected_value": 0.01, "unit": "p-value", "tolerance": null, "state": "complete", "note": "The threshold the paper applied to its own result, as the paper states it. A run that reproduces the effect is judged against this threshold."}], "gaps": ["method", "operations"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"tier": "R4", "expressible": false, "required_operations": [], "missing_operations": [], "basis": "The reader quoted the method the paper names (not named), but the corpus's method extractor could not map it onto a DSL operation, so the method is published but not expressible."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R4", "reachable": false, "accessions": [], "resolved_accessions": [], "statements": [], "basis": "The paper names no accession to its source data, so the data has to come from the authors."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:24302499"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:21:50Z", "independence": "single_reader"}, "evidence_check": {"method": null, "availability": null}, "calls": 2, "usage": {"prompt_tokens": 16372, "completion_tokens": 1377, "cached_tokens": 528}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:24302499", "type": "paper", "label": "pmid:24302499"}, {"id": "source:pmid:24302499", "type": "manuscript", "label": "PMID 24302499 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:24302499", "type": "paper", "label": "pmid:24302499"}, {"id": "source:pmid:24302499", "type": "manuscript", "label": "PMID 24302499 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-24302499", "type": "extraction", "used": ["source:pmid:24302499"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:24302499", "parent_hash": "sha256:38963e22bd8d374d88226fe4d02fff4ad3b15aeac169252fd0b86d2ba65de8fb", "fork_of": null, "generation": 1}, "gaps": ["execution.not_run", "method", "operations", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent"], "assays": [{"role": "data_generation", "definition_id": "mass_spectrometry", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["microdissection and subsequently analyzed by LC-MS/MS. Proteolytic processing of TGFBIp was addres", "causes structural changes of TGFBIp. The MS proteomics data have been deposited to the ProteomeXcha"], "order_basis": "paper_text_order:822", "id": "assay:1"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["tered corneal amyloid composition or altered in vivo proteolytic processing of TGFBIp. Instead, a"], "order_basis": "paper_text_order:1662", "id": "assay:2"}]}