A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy
Abstract Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a...
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| Format: | Article |
| Language: | English |
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BMC
2020-06-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-020-00975-w |
| _version_ | 1828852141112950784 |
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| author | Valentina Baderna Joshua Schultz Lisa S. Kearns Michael Fahey Bryony A. Thompson Jonathan B. Ruddle Aamira Huq Francesca Maltecca |
| author_facet | Valentina Baderna Joshua Schultz Lisa S. Kearns Michael Fahey Bryony A. Thompson Jonathan B. Ruddle Aamira Huq Francesca Maltecca |
| author_sort | Valentina Baderna |
| collection | DOAJ |
| description | Abstract Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA. |
| first_indexed | 2024-12-12T23:46:43Z |
| format | Article |
| id | doaj.art-10706826b7434e968105f1c716e20d3f |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-12T23:46:43Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-10706826b7434e968105f1c716e20d3f2022-12-22T00:06:49ZengBMCActa Neuropathologica Communications2051-59602020-06-01811810.1186/s40478-020-00975-wA novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophyValentina Baderna0Joshua Schultz1Lisa S. Kearns2Michael Fahey3Bryony A. Thompson4Jonathan B. Ruddle5Aamira Huq6Francesca Maltecca7Mitochondrial dysfunctions in neurodegeneration Unit, Division of Neuroscience, Ospedale San RaffaeleParkville Familial Cancer and Genomic Medicine Department, The Royal Melbourne HospitalCentre for Eye ResearchParkville Familial Cancer and Genomic Medicine Department, The Royal Melbourne HospitalDepartment of Pathology, The Royal Melbourne HospitalCentre for Eye ResearchParkville Familial Cancer and Genomic Medicine Department, The Royal Melbourne HospitalMitochondrial dysfunctions in neurodegeneration Unit, Division of Neuroscience, Ospedale San RaffaeleAbstract Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.http://link.springer.com/article/10.1186/s40478-020-00975-wAFG3L2OPA1Optic atrophyMitochondrial fragmentation |
| spellingShingle | Valentina Baderna Joshua Schultz Lisa S. Kearns Michael Fahey Bryony A. Thompson Jonathan B. Ruddle Aamira Huq Francesca Maltecca A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy Acta Neuropathologica Communications AFG3L2 OPA1 Optic atrophy Mitochondrial fragmentation |
| title | A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy |
| title_full | A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy |
| title_fullStr | A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy |
| title_full_unstemmed | A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy |
| title_short | A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy |
| title_sort | novel afg3l2 mutation close to aaa domain leads to aberrant oma1 and opa1 processing in a family with optic atrophy |
| topic | AFG3L2 OPA1 Optic atrophy Mitochondrial fragmentation |
| url | http://link.springer.com/article/10.1186/s40478-020-00975-w |
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