Clinical and Structural Characterization of a Novel TGFBI Mutation Linked to a Lattice Corneal Dystrophy Variant in a Greek Family.
| Title: | Clinical and Structural Characterization of a Novel TGFBI Mutation Linked to a Lattice Corneal Dystrophy Variant in a Greek Family. |
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| Authors: | Zacharogianni M; From the Independent Author (M.Z.).; Papandreou NC; Department of Biology, School of Sciences (N.C.P.), Section of Cell Biology and Biophysics, National and Kapodistrian University of Athens, Athens, Greece.; Marinakis NM; Laboratory of Medical Genetics (N.M.M., F.N.T., and J.T.S.), St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece; Research University Institute for the Study and Prevention of Genetic and Malignant Disease of Childhood (N.M.M.), St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Tilemis FN; Laboratory of Medical Genetics (N.M.M., F.N.T., and J.T.S.), St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Traeger-Synodinos J; Laboratory of Medical Genetics (N.M.M., F.N.T., and J.T.S.), St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.; Palioura S; Department of Ophthalmology (S.P.), University of Cyprus Medical School, Nicosia, Cyprus. Electronic address: sotiria.palioura@gmail.com. |
| Source: | American journal of ophthalmology [Am J Ophthalmol] 2025 Jun; Vol. 274, pp. 112-121. Date of Electronic Publication: 2025 Mar 04. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 0370500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1891 (Electronic) Linking ISSN: 00029394 NLM ISO Abbreviation: Am J Ophthalmol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1999- : New York, NY : Elsevier Science; Original Publication: [Chicago, etc., Ophthalmic Pub. Co., etc.] |
| MeSH Terms: | Corneal Dystrophies, Hereditary*/genetics ; Corneal Dystrophies, Hereditary*/diagnosis ; Corneal Dystrophies, Hereditary*/metabolism ; Extracellular Matrix Proteins*/genetics ; Extracellular Matrix Proteins*/metabolism ; Transforming Growth Factor beta*/genetics ; Transforming Growth Factor beta*/metabolism ; Mutation*; Greece/epidemiology ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Case-Control Studies ; DNA Mutational Analysis ; Exome Sequencing ; Genetic Association Studies ; Pedigree ; Phenotype ; Slit Lamp Microscopy ; Tomography, Optical Coherence ; betaIG-H3 Protein |
| Abstract: | Purpose: To describe a novel pathogenic TGFBI variant identified in a Greek family and investigate its structural impact on the TGFBI protein, focusing on clinical significance and genotype-phenotype correlations.; Design: Single-family case-control study with computational structural analysis.; Methods: Three generations of a Greek family, including the proband, her brother, and their mother were clinically evaluated using slit-lamp examination and anterior segment optical coherence tomography. Whole exome sequencing was performed on the proband, followed by targeted sequencing of family members. Bioinformatics tools, including DynaMut2, PROVEAN, and AlphaFold2, were used to predict the mutation's impact on protein structure and stability.; Results: A novel heterozygous variant, c.1517_1518insCCCCCCCAAGGG, was identified. This 12-nucleotide insertion replaces methionine at position 506 with isoleucine, proline, proline, lysine, and glycine (p.M506delinsIPPKG). Clinically, this mutation was associated with geographic subepithelial and anterior stromal opacities without discernible lattice lines and presented as recurrent corneal erosions in the second decade. Structural analysis revealed disruption of the first α-helix of the FAS1-4 domain, destabilizing the protein and potentially exposing amyloidogenic regions. Previously reported mutations within this α-helix consistently produce a phenotype of geographic subepithelial opacities and a similar age of onset.; Conclusions: M506delinsIPPKG represents a novel pathogenic TGFBI variant associated with an autosomal dominant lattice corneal dystrophies variant. The structural disruption of the FAS1-4 domain's α-helix likely underlies the disease mechanism and links structural changes to specific phenotypic traits. These findings contribute to our understanding of genotype-phenotype correlations in TGFBI-related corneal dystrophies and highlight the importance of structural analysis in such cases.; (Copyright © 2025 Elsevier Inc. All rights reserved.) |
| Substance Nomenclature: | 0 (Extracellular Matrix Proteins); 0 (Transforming Growth Factor beta); 0 (betaIG-H3 Protein) |
| SCR Disease Name: | Lattice corneal dystrophy type 1 |
| Entry Date(s): | Date Created: 20250306 Date Completed: 20250501 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.ajo.2025.03.003 |
| PMID: | 40049267 |
| Database: | MEDLINE |
Journal Article