TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation

TL;DR

This study investigates a rare eye disease called gelatinous drop-like corneal dystrophy (GDLD), focusing on a genetic variant in the TACSTD2 gene and its role in amyloid buildup in the cornea, even after a stem cell transplant.

Contribution

The study provides experimental evidence that amyloid recurrence in GDLD can occur after limbal stem cell transplantation despite normal TACSTD2 expression in donor cells.

Findings

A homozygous deletion in the TACSTD2 gene was found in a GDLD patient, leading to loss of transmembrane domain and protein mislocalization.

Post-transplant corneal samples showed wild-type TACSTD2 expression in donor cells, but amyloid deposition still occurred.

The recurrence of amyloid suggests that donor cell replacement alone may not prevent disease progression in GDLD.

Abstract

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.

Gelatinous drop-like corneal dystrophy is a rare eye disease passed down through families, causing vision loss due to a protein called amyloid building up in the cornea, the clear front surface of the eye. This study looks into the genes related to GDLD, focusing on a specific gene variant in TACSTD2, which is involved in the disease. Through sequencing of a patient’s DNA, the team found a variant in TACSTD2 linked to the protein buildup in GDLD. Results showed that despite successful LSCT, the protein built up again, indicating that replacing damaged cells with healthy ones might not prevent recurrence. The study concludes that the TACSTD2 variant contributes to GDLD by disrupting normal protein function, leading to protein buildup. This insight improves our understanding of GDLD and suggests that future treatments need to address the genetic causes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

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