Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 30, Issue 7, Pages 848-855Publisher
SPRINGERNATURE
DOI: 10.1038/s41431-022-01102-0
Keywords
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Funding
- Moorfields Eye Charity Research Training Fellowship
- Wellcome Trust
- Foundation Fighting Blindness (United States)
- Moorfields Eye Charity
- Fight for Sight [NIHR301696]
- UK National Institute of Health Research (NIHR)
- Medical Research Council (United Kingdom)
- Fight for Sight (United Kingdom)
- Isaac Newton Trust (United Kingdom)
- Addenbrooke's Charitable Trust
- National Eye Research Centre (United Kingdom)
- International Foundation for Optic Nerve Disease (IFOND)
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20,014]
- NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust
- UCL Institute of Ophthalmology
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Autosomal dominant optic atrophy (DOA) is a genetic optic neuropathy caused by OPA1 gene mutations. This study reports a novel splice variant in the OPA1 gene that leads to severe clinical manifestations and impaired mitochondrial function in a patient with DOA+.
Autosomal dominant optic atrophy (DOA) is an inherited optic neuropathy that results in progressive, bilateral visual acuity loss and field defects. OPA1 is the causative gene in around 60% of cases of DOA. The majority of patients have a pure ocular phenotype, but 20% have extra-ocular features (DOA +). We report on a patient with DOA + manifesting as bilateral optic atrophy, spastic paraparesis, urinary incontinence and white matter changes in the central nervous system associated with a novel heterozygous splice variant NM_015560.2(0PA1):c.2356-1 G > T. Further characterisation, which was performed using fibroblasts obtained from a skin biopsy, demonstrated that this variant altered mRNA splicing of the OPA1 transcript, specifically a 21 base pair deletion at the start of exon 24, NM_015560.2(OPA1):p.Cys786_Lys792del. The majority of variant transcripts were shown to escape nonsensemediated decay and modelling of the predicted protein structure suggests that the in-frame 7 amino acid deletion may affect OPA1 oligomerisation. Fibroblasts carrying the c.2356-1 G > T variant demonstrated impaired mitochondrial bioenergetics, membrane potential, increased cell death, and disrupted and fragmented mitochondrial networks in comparison to WT cells. This study suggests that the c.2356-1 G >T OPA1 splice site variant leads to a cryptic splice site activation and may manifest in a dominantnegative manner, which could account for the patient's severe syndromic phenotype.
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