Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC)
Leigh syndrome French Canadian type (LSFC) is a recessive neurodegenerative disease characterized by tissue-specific deficiency in cytochrome c oxidase (COX), the fourth complex in the oxidative phosphorylation system. LSFC is caused by mutations in the leucine rich pentatricopeptide repeat containi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1375467/full |
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| author | Roselle Gélinas Chloé Lévesque Julie Thompson Legault Marie-Eve Rivard Louis Villeneuve Catherine Laprise John D. Rioux John D. Rioux |
| author_facet | Roselle Gélinas Chloé Lévesque Julie Thompson Legault Marie-Eve Rivard Louis Villeneuve Catherine Laprise John D. Rioux John D. Rioux |
| author_sort | Roselle Gélinas |
| collection | DOAJ |
| description | Leigh syndrome French Canadian type (LSFC) is a recessive neurodegenerative disease characterized by tissue-specific deficiency in cytochrome c oxidase (COX), the fourth complex in the oxidative phosphorylation system. LSFC is caused by mutations in the leucine rich pentatricopeptide repeat containing gene (LRPPRC). Most LSFC patients in Quebec are homozygous for an A354V substitution that causes a decrease in the expression of the LRPPRC protein. While LRPPRC is ubiquitously expressed and is involved in multiple cellular functions, tissue-specific expression of LRPPRC and COX activity is correlated with clinical features. In this proof-of-principle study, we developed human induced pluripotent stem cell (hiPSC)-based models from fibroblasts taken from a patient with LSFC, homozygous for the LRPPRC*354V allele, and from a control, homozygous for the LRPPRC*A354 allele. Specifically, for both of these fibroblast lines we generated hiPSC, hiPSC-derived cardiomyocytes (hiPSC-CMs) and hepatocyte-like cell (hiPSC-HLCs) lines, as well as the three germ layers. We observed that LRPPRC protein expression is reduced in all cell lines/layers derived from LSFC patient compared to control cells, with a reduction ranging from ∼70% in hiPSC-CMs to undetectable levels in hiPSC-HLC, reflecting tissue heterogeneity observed in patient tissues. We next performed exploratory analyses of these cell lines and observed that COX protein expression was reduced in all cell lines derived from LSFC patient compared to control cells. We also observed that mutant LRPPRC was associated with altered expression of key markers of endoplasmic reticulum stress response in hiPSC-HLCs but not in other cell types that were tested. While this demonstrates feasibility of the approach to experimentally study genotype-based differences that have tissue-specific impacts, this study will need to be extended to a larger number of patients and controls to not only validate the current observations but also to delve more deeply in the pathogenic mechanisms of LSFC. |
| first_indexed | 2024-04-24T07:44:43Z |
| format | Article |
| id | doaj.art-8e98851c8f244ed8b792433bcf54a932 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-24T07:44:43Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-8e98851c8f244ed8b792433bcf54a9322024-04-19T04:37:53ZengFrontiers Media S.A.Frontiers in Genetics1664-80212024-04-011510.3389/fgene.2024.13754671375467Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC)Roselle Gélinas0Chloé Lévesque1Julie Thompson Legault2Marie-Eve Rivard3Louis Villeneuve4Catherine Laprise5John D. Rioux6John D. Rioux7Montreal Heart Institute, Montreal, QC, CanadaMontreal Heart Institute, Montreal, QC, CanadaMontreal Heart Institute, Montreal, QC, CanadaMontreal Heart Institute, Montreal, QC, CanadaMontreal Heart Institute, Montreal, QC, CanadaUniversité du Québec à Chicoutimi, Saguenay, QC, CanadaMontreal Heart Institute, Montreal, QC, CanadaUniversité de Montréal, Montreal, QC, CanadaLeigh syndrome French Canadian type (LSFC) is a recessive neurodegenerative disease characterized by tissue-specific deficiency in cytochrome c oxidase (COX), the fourth complex in the oxidative phosphorylation system. LSFC is caused by mutations in the leucine rich pentatricopeptide repeat containing gene (LRPPRC). Most LSFC patients in Quebec are homozygous for an A354V substitution that causes a decrease in the expression of the LRPPRC protein. While LRPPRC is ubiquitously expressed and is involved in multiple cellular functions, tissue-specific expression of LRPPRC and COX activity is correlated with clinical features. In this proof-of-principle study, we developed human induced pluripotent stem cell (hiPSC)-based models from fibroblasts taken from a patient with LSFC, homozygous for the LRPPRC*354V allele, and from a control, homozygous for the LRPPRC*A354 allele. Specifically, for both of these fibroblast lines we generated hiPSC, hiPSC-derived cardiomyocytes (hiPSC-CMs) and hepatocyte-like cell (hiPSC-HLCs) lines, as well as the three germ layers. We observed that LRPPRC protein expression is reduced in all cell lines/layers derived from LSFC patient compared to control cells, with a reduction ranging from ∼70% in hiPSC-CMs to undetectable levels in hiPSC-HLC, reflecting tissue heterogeneity observed in patient tissues. We next performed exploratory analyses of these cell lines and observed that COX protein expression was reduced in all cell lines derived from LSFC patient compared to control cells. We also observed that mutant LRPPRC was associated with altered expression of key markers of endoplasmic reticulum stress response in hiPSC-HLCs but not in other cell types that were tested. While this demonstrates feasibility of the approach to experimentally study genotype-based differences that have tissue-specific impacts, this study will need to be extended to a larger number of patients and controls to not only validate the current observations but also to delve more deeply in the pathogenic mechanisms of LSFC.https://www.frontiersin.org/articles/10.3389/fgene.2024.1375467/fullinduced pluripotent stem cellsthree germ layershepatocyte-like cellscardiomyocyte cellsdisease modelingLeigh syndrome French Canadian type |
| spellingShingle | Roselle Gélinas Chloé Lévesque Julie Thompson Legault Marie-Eve Rivard Louis Villeneuve Catherine Laprise John D. Rioux John D. Rioux Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC) Frontiers in Genetics induced pluripotent stem cells three germ layers hepatocyte-like cells cardiomyocyte cells disease modeling Leigh syndrome French Canadian type |
| title | Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC) |
| title_full | Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC) |
| title_fullStr | Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC) |
| title_full_unstemmed | Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC) |
| title_short | Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC) |
| title_sort | human induced pluripotent stem cells hipscs derived cells reflect tissue specificity found in patients with leigh syndrome french canadian variant lsfc |
| topic | induced pluripotent stem cells three germ layers hepatocyte-like cells cardiomyocyte cells disease modeling Leigh syndrome French Canadian type |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1375467/full |
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