CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy
Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) is a severe recessive inherited disease, causing muscular degeneration and retinochoroidal atrophy that progresses to blindness. HOGA arises from mutations in the ornithine aminotransferase (OAT) gene, and nearly one-third of the...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426922000234 |
| _version_ | 1819022805462679552 |
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| author | Rocio Maldonado Sami Jalil Timo Keskinen Anni I. Nieminen Mervi E. Hyvönen Risto Lapatto Kirmo Wartiovaara |
| author_facet | Rocio Maldonado Sami Jalil Timo Keskinen Anni I. Nieminen Mervi E. Hyvönen Risto Lapatto Kirmo Wartiovaara |
| author_sort | Rocio Maldonado |
| collection | DOAJ |
| description | Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) is a severe recessive inherited disease, causing muscular degeneration and retinochoroidal atrophy that progresses to blindness. HOGA arises from mutations in the ornithine aminotransferase (OAT) gene, and nearly one-third of the known patients worldwide are homozygous for the Finnish founder mutation OAT c.1205 T > C p.(Leu402Pro). We have corrected this loss-of-function OAT mutation in patient-derived induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. The correction restored OAT expression in stem cells and normalized the elevated ornithine levels in cell lysates and cell media. These results show an efficient recovery of OAT function in iPSC, encouraging the possibility of autologous cell therapy for the HOGA disease. |
| first_indexed | 2024-12-21T04:28:50Z |
| format | Article |
| id | doaj.art-587f0cdc36a4415e9fccd848fc8523ef |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-21T04:28:50Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-587f0cdc36a4415e9fccd848fc8523ef2022-12-21T19:15:59ZengElsevierMolecular Genetics and Metabolism Reports2214-42692022-06-0131100863CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophyRocio Maldonado0Sami Jalil1Timo Keskinen2Anni I. Nieminen3Mervi E. Hyvönen4Risto Lapatto5Kirmo Wartiovaara6Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandMetabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, FinlandStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Clinical Genetics, Helsinki University Hospital, Helsinki, Finland; Corresponding author at: Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) is a severe recessive inherited disease, causing muscular degeneration and retinochoroidal atrophy that progresses to blindness. HOGA arises from mutations in the ornithine aminotransferase (OAT) gene, and nearly one-third of the known patients worldwide are homozygous for the Finnish founder mutation OAT c.1205 T > C p.(Leu402Pro). We have corrected this loss-of-function OAT mutation in patient-derived induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. The correction restored OAT expression in stem cells and normalized the elevated ornithine levels in cell lysates and cell media. These results show an efficient recovery of OAT function in iPSC, encouraging the possibility of autologous cell therapy for the HOGA disease.http://www.sciencedirect.com/science/article/pii/S2214426922000234CRISPR/Cas9gene editinggyrate atrophyHOGA OAT |
| spellingShingle | Rocio Maldonado Sami Jalil Timo Keskinen Anni I. Nieminen Mervi E. Hyvönen Risto Lapatto Kirmo Wartiovaara CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy Molecular Genetics and Metabolism Reports CRISPR/Cas9 gene editing gyrate atrophy HOGA OAT |
| title | CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy |
| title_full | CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy |
| title_fullStr | CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy |
| title_full_unstemmed | CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy |
| title_short | CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy |
| title_sort | crispr correction of the finnish ornithine delta aminotransferase mutation restores metabolic homeostasis in ipsc from patients with gyrate atrophy |
| topic | CRISPR/Cas9 gene editing gyrate atrophy HOGA OAT |
| url | http://www.sciencedirect.com/science/article/pii/S2214426922000234 |
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