ArticleThe Journal of clinical investigation2022
Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Pooled it
- Lycorine inhibits the proliferation of acute myeloid leukemia cells by upregulating the expression of THBS1.Annals of hematology · 2026Article
- Challenge of Corneal Ulcer Healing: A Novel Conceptual Framework, the "Triad" of Corneal Ulcer Healing/Corneal Neovascularization/Intraocular Pressure, and Avascular Tendon Healing, for Evaluation of Corneal Ulcer Therapy, Therapy of Neovascularization, Glaucoma Therapy, and Pentadecapeptide BPC 157 Efficacy.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Hypomethylation of thrombospondin-1 promoter region is associated with reduced aqueous humor flow.Communications biology · 2025Article
- Thrombospondin-1 inhibits alternative complement pathway activation in antineutrophil cytoplasmic antibody-associated vasculitis.The Journal of clinical investigation · 2025Article
- Preserving blood-retinal barrier integrity: a path to retinal ganglion cell protection in glaucoma and traumatic optic neuropathy.Cell regeneration (London, England) · 2025Review
- Progress in Translating Glaucoma Genetics Into the Clinic: A Review.Clinical & experimental ophthalmology · 2025Review
- Thrombospondins: Conserved mediators and modulators of metazoan extracellular matrix.International journal of experimental pathology · 2024Review
- Potential Involvements of Cilia-Centrosomal Genes in Primary Congenital Glaucoma.International journal of molecular sciences · 2024Article
- Congenital anterior segment ocular disorders: Genotype-phenotype correlations and emerging novel mechanisms.Progress in retinal and eye research · 2024Review
- Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project.BMC genomics · 2024Article
- Influence of the calcium voltage-gated channel auxiliary subunit (CACNA2D1) absence on intraocular pressure in mice.Experimental eye research · 2024Article
- Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives.International journal of molecular sciences · 2023Review
- Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Transcriptomic Analysis of the Ocular Posterior Segment Completes a Cell Atlas of the Human Eye.bioRxiv : the preprint server for biology · 2023Article
- Glial cells as a promising therapeutic target of glaucoma: beyond the IOP.Frontiers in ophthalmology · 2023Review
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
Abstract
Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Extracellular matrix (ECM) proteins, especially fibronectin, which bind to THBS1, also accumulated within THBS1 deposits. These results show that missense variants altering THBS1 p.Arg1034 can cause elevated IOP through a mechanism involving impaired TM fluid outflow in association with accumulation of aggregated THBS1 in the ECM of juxtacanalicular meshwork with altered morphology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.