TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation
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) ha...
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| Format: | Article |
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Nature Publishing Group
2024-07-01
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| Series: | Human Genome Variation |
| Online Access: | https://doi.org/10.1038/s41439-024-00284-x |
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| author | Liubov O. Skorodumova Ekaterina N. Grafskaia Daria D. Kharlampieva Dmitry I. Maltsev Tatiana V. Petrova Alexandra V. Kanygina Elena V. Fedoseeva Pavel V. Makarov Boris E. Malyugin |
| author_facet | Liubov O. Skorodumova Ekaterina N. Grafskaia Daria D. Kharlampieva Dmitry I. Maltsev Tatiana V. Petrova Alexandra V. Kanygina Elena V. Fedoseeva Pavel V. Makarov Boris E. Malyugin |
| author_sort | Liubov O. Skorodumova |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-82e92ab73f3141678c61e3b1db5c5e92 |
| institution | Kabale University |
| issn | 2054-345X |
| language | English |
| publishDate | 2024-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Human Genome Variation |
| spelling | doaj-art-82e92ab73f3141678c61e3b1db5c5e922025-01-19T12:15:56ZengNature Publishing GroupHuman Genome Variation2054-345X2024-07-011111710.1038/s41439-024-00284-xTACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantationLiubov O. Skorodumova0Ekaterina N. Grafskaia1Daria D. Kharlampieva2Dmitry I. Maltsev3Tatiana V. Petrova4Alexandra V. Kanygina5Elena V. Fedoseeva6Pavel V. Makarov7Boris E. Malyugin8Laboratory of Human Molecular Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyLaboratory of Genetic Engineering, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyLaboratory of Genetic Engineering, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyLaboratory of Neurotechnology, Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological AgencyLaboratory of Human Molecular Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyLaboratory of Human Molecular Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyDepartment of Trauma and Reconstructive Surgery, Helmholtz National Medical Research Center of Eye DiseasesDepartment of Trauma and Reconstructive Surgery, Helmholtz National Medical Research Center of Eye DiseasesDepartment of Anterior Segment Transplant and Optical Reconstructive Surgery, S. Fyodorov Eye Microsurgery Complex Federal State InstitutionAbstract 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.https://doi.org/10.1038/s41439-024-00284-x |
| spellingShingle | Liubov O. Skorodumova Ekaterina N. Grafskaia Daria D. Kharlampieva Dmitry I. Maltsev Tatiana V. Petrova Alexandra V. Kanygina Elena V. Fedoseeva Pavel V. Makarov Boris E. Malyugin TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation Human Genome Variation |
| title | TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation |
| title_full | TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation |
| title_fullStr | TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation |
| title_full_unstemmed | TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation |
| title_short | TACSTD2 in gelatinous drop-like corneal dystrophy: variant functional analysis and expression in the cornea after limbal stem cell transplantation |
| title_sort | tacstd2 in gelatinous drop like corneal dystrophy variant functional analysis and expression in the cornea after limbal stem cell transplantation |
| url | https://doi.org/10.1038/s41439-024-00284-x |
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