膠様滴状角膜ジストロフィー

Claudin-1, a transmembrane protein integral to tight junctions, is indispensable for paracellular barrier formation and the establishment and maintenance of cellular polarity. In the eye, claudin-1 exhibits tissue-specific expression in critical structures such as the cornea and retina, where it contributes fundamentally to corneal transparency, blood-retinal barrier integrity, and retinal homeostasis. This review comprehensively synthesizes current knowledge on the spatial distribution and physiological roles of claudin-1 across ocular tissues. We critically evaluate recent mechanistic and translational advances implicating claudin-1 dysregulation in a spectrum of ocular pathologies: anterior segment disorders (dry eye disease, pterygium, infectious keratitis, and gelatinous drop-like corneal dystrophy), retinal diseases (diabetic retinopathy, age-related macular degeneration, central serous chorioretinopathy, and retinoblastoma), and other conditions (uveitis, glaucoma, post-cataract macular edema, and cataract). Finally, we assess the emerging therapeutic potential of claudin-1-both as a molecular target for barrier modulation and as a facilitator of paracellular drug delivery in ophthalmology.

BACKGROUND: Gelatinous drop-like dystrophy is a rare autosomal recessive disorder caused by pathogenic variants in the TACSTD2 gene and characterized by subepithelial amyloid deposits in the cornea. Alterations in FOXC2 are seen in lymphedema-distichiasis syndrome, in which patients classically exhibit lymphedema of the extremities and a double row of eyelashes. This report links alterations in the FOXC2 gene to a corneal phenotype that is histologically identical to that seen in gelatinous drop-like dystrophy. CASE PRESENTATION: A 14-year-old male with congenital distichiasis presented with chronic photosensitivity and progressively worsening vision over several years. On examination, gelatinous-appearing lesions were observed on the inferior third of each cornea with neovascularization. Genetic testing identified a likely pathogenic alteration in FOXC2, a gene linked to lymphedema-distichiasis syndrome. No genetic alterations of corneal dystrophy were identified. The patient underwent excisions of the corneal lesions with simple limbal epithelial transplant, amniotic membrane transplant and temporary central tarsorrhaphy. The pathologic features of the corneal lesions resembled gelatinous drop-like dystrophy. One side was free of inflammation, while the other side showed a granulomatous response to the amyloid, which is unusual in this site. Potential pathogenic and clearance mechanisms are discussed. There has been no recurrence of the corneal lesions in approximately 3 years of follow-up. CONCLUSIONS: This case presents a new link between FOXC2 alterations and a histological phenotype that resembles gelatinous drop-like dystrophy (GDLD-like), emphasizing the importance of clinical, pathologic, and molecular correlation. Granulomatous responses to amyloid are unusual in this immune privileged site.

PURPOSE: To report a case of gelatinous drop-like corneal dystrophy (GDLD) caused by a novel homozygous tumor-associated calcium signal transducer 2 ( TACSTD2 ) gene mutation and summarize the correlations of clinical phenotypes and genotypes in patients with GDLD. METHODS: We analyzed the clinical characteristics and treatment outcomes of a 42-year-old man with GDLD. The patient with GDLD received multiple keratoplasties, and histopathological staining of the corneal sections was performed. We performed genetic testing and clinical evaluations on all family members. In addition, we conducted a literature review of previously reported patients with GDLD with pathogenic TACSTD2 gene mutations. RESULTS: Genetic sequencing of the proband identified a novel nonsense homozygous mutation c.588C > A in the TACSTD2 gene. The histopathological analysis revealed intense amyloid deposition in the subepithelial region of the cornea. We summarized the clinical features of patients with GDLD with 33 previously reported TACSTD2 gene mutations. CONCLUSIONS: This study reported a novel homozygous nonsense mutation in a Chinese patient with GDLD, thereby expanding the mutation spectrum of the TACSTD2 gene.

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive eye disease. GDLD is characterized by the loss of barrier function in corneal epithelial cells (CECs) and amyloid deposition due to pathogenic variants in the TACSTD2 gene. Limbal stem cell transplantation (LSCT) has been suggested as an effective therapeutic alternative for patients with GDLD. However, despite LSCT, amyloid deposition recurs in some patients. The pathogenesis of recurrence is poorly studied. We present the case of a patient with GDLD. Genetic analysis revealed a homozygous deletion, NM_002353.3:c.653del, in the TACSTD2 gene. Functional analysis in a cell model system revealed the loss of the transmembrane domain and subcellular protein mislocalization. The patient with GDLD underwent direct allogeneic LSCT with epithelial debridement followed by deep anterior lamellar keratoplasty 10 months later due to amyloid deposition and deterioration of vision. Taken together, the results of transcriptome analysis and immunofluorescence staining of post-LSCT corneal sample with amyloid deposits obtained during keratoplasty demonstrated complete restoration of wild-type TACSTD2 expression, indicating that donor CECs replaced host CECs. Our study provides experimental evidence that amyloid deposition can recur after LSCT despite complete restoration of wild-type TACSTD2 expression.

Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER-localized eukaryotic glycoprotein secretion checkpoint, UDP-glucose glycoprotein glucosyl-transferase (UGGT). The enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re-glucosylating one of its N-linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT-mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity ("responsive mutant"). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop-2-Q118E, E227K and L186P mutants, which cause gelatinous drop-like corneal dystrophy (GDLD). Compared with the wild-type Trop-2, which is correctly localized at the plasma membrane, these Trop-2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop-2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9-mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop-2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1-/- cells. UGGT1 also efficiently reglucosylated Trop-2-Q118E-EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad-spectrum rescue-of-secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.