Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis
Dominant optic atrophy (DOA) is mainly caused by OPA1 mutations and is characterized by the degeneration of retinal ganglion cells (RGCs), whose axons form the optic nerve. The penetrance of DOA is incomplete and the disease is marked by highly variable expressivity, ranging from asymptomatic patien...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-09-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1241222/full |
| _version_ | 1827823341387382784 |
|---|---|
| author | Djamaa Atamena Venu Gurram Petnoï Petsophonsakul Farnoosh Khosrobakhsh Farnoosh Khosrobakhsh Macarena S. Arrázola Marlène Botella Bernd Wissinger Marion Szelechowski Pascale Belenguer |
| author_facet | Djamaa Atamena Venu Gurram Petnoï Petsophonsakul Farnoosh Khosrobakhsh Farnoosh Khosrobakhsh Macarena S. Arrázola Marlène Botella Bernd Wissinger Marion Szelechowski Pascale Belenguer |
| author_sort | Djamaa Atamena |
| collection | DOAJ |
| description | Dominant optic atrophy (DOA) is mainly caused by OPA1 mutations and is characterized by the degeneration of retinal ganglion cells (RGCs), whose axons form the optic nerve. The penetrance of DOA is incomplete and the disease is marked by highly variable expressivity, ranging from asymptomatic patients to some who are totally blind or who suffer from multisystemic effects. No clear genotype–phenotype correlation has been established to date. Taken together, these observations point toward the existence of modifying genetic and/or environmental factors that modulate disease severity. Here, we investigated the influence of genetic background on DOA expressivity by switching the previously described DOA mouse model bearing the c.1065 + 5G → A Opa1 mutation from mixed C3H; C57BL/6 J to a pure C57BL/6 J background. We no longer observed retinal and optic nerve abnormalities; the findings indicated no degeneration, but rather a sex-dependent negative effect on RGC connectivity. This highlights the fact that RGC synaptic alteration might precede neuronal death, as has been proposed in other neurodegenerative diseases, providing new clinical considerations for early diagnosis as well as a new therapeutic window for DOA. Furthermore, our results demonstrate the importance of secondary genetic factors in the variability of DOA expressivity and offer a model for screening for aggravating environmental and genetic factors. |
| first_indexed | 2024-03-12T02:10:43Z |
| format | Article |
| id | doaj.art-fee25e707cac4f04b6fc102071611092 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-12T02:10:43Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-fee25e707cac4f04b6fc1020716110922023-09-06T14:21:05ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-09-011610.3389/fnmol.2023.12412221241222Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesisDjamaa Atamena0Venu Gurram1Petnoï Petsophonsakul2Farnoosh Khosrobakhsh3Farnoosh Khosrobakhsh4Macarena S. Arrázola5Marlène Botella6Bernd Wissinger7Marion Szelechowski8Pascale Belenguer9Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceDepartment of Biological Science, University of Kurdistan, Sanandaj, IranCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceInstitute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, GermanyCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceCentre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Toulouse III, CNRS, Toulouse, FranceDominant optic atrophy (DOA) is mainly caused by OPA1 mutations and is characterized by the degeneration of retinal ganglion cells (RGCs), whose axons form the optic nerve. The penetrance of DOA is incomplete and the disease is marked by highly variable expressivity, ranging from asymptomatic patients to some who are totally blind or who suffer from multisystemic effects. No clear genotype–phenotype correlation has been established to date. Taken together, these observations point toward the existence of modifying genetic and/or environmental factors that modulate disease severity. Here, we investigated the influence of genetic background on DOA expressivity by switching the previously described DOA mouse model bearing the c.1065 + 5G → A Opa1 mutation from mixed C3H; C57BL/6 J to a pure C57BL/6 J background. We no longer observed retinal and optic nerve abnormalities; the findings indicated no degeneration, but rather a sex-dependent negative effect on RGC connectivity. This highlights the fact that RGC synaptic alteration might precede neuronal death, as has been proposed in other neurodegenerative diseases, providing new clinical considerations for early diagnosis as well as a new therapeutic window for DOA. Furthermore, our results demonstrate the importance of secondary genetic factors in the variability of DOA expressivity and offer a model for screening for aggravating environmental and genetic factors.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1241222/fulloptic atrophyOPA1mitochondriagenetic modifiersdisease severitymouse strains |
| spellingShingle | Djamaa Atamena Venu Gurram Petnoï Petsophonsakul Farnoosh Khosrobakhsh Farnoosh Khosrobakhsh Macarena S. Arrázola Marlène Botella Bernd Wissinger Marion Szelechowski Pascale Belenguer Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis Frontiers in Molecular Neuroscience optic atrophy OPA1 mitochondria genetic modifiers disease severity mouse strains |
| title | Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis |
| title_full | Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis |
| title_fullStr | Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis |
| title_full_unstemmed | Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis |
| title_short | Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis |
| title_sort | genetic background modulates phenotypic expressivity in opa1 mutated mice relevance to doa pathogenesis |
| topic | optic atrophy OPA1 mitochondria genetic modifiers disease severity mouse strains |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1241222/full |
| work_keys_str_mv | AT djamaaatamena geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT venugurram geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT petnoipetsophonsakul geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT farnooshkhosrobakhsh geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT farnooshkhosrobakhsh geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT macarenasarrazola geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT marlenebotella geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT berndwissinger geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT marionszelechowski geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis AT pascalebelenguer geneticbackgroundmodulatesphenotypicexpressivityinopa1mutatedmicerelevancetodoapathogenesis |