Solving a 50 year mystery of a missing OPA1 mutation: more insights from the first family diagnosed with autosomal dominant optic atrophy

Abstract

BackgroundUp to the 1950s, there was an ongoing debate about the diversity of hereditary optic neuropathies, in particular as to whether all inherited optic atrophies can be ascribed to Leber's hereditary optic neuropathy (LHON) or represent different disease entities. In 1954 W. Jaeger published a detailed clinical and genealogical investigation of a large family with explicit autosomal dominant segregation of optic atrophy thus proving the existence of a discrete disease different from LHON, which is nowadays known as autosomal dominant optic atrophy (ADOA). Since the year 2000 ADOA is associated with genomic mutations in the OPA1 gene, which codes for a protein that is imported into mitochondria where it is required for mitochondrial fusion. Interestingly enough, the underlying mutation in this family has not been identified since then.ResultsWe have reinvestigated this family with the aim to identify the mutation and to further clarify the underlying pathomechanism. Patients showed a classical non-syndromic ADOA. The long term deterioration in vision in the two teenagers examined 50 years later is of particular note 5/20 to 6/120. Multiplex ligation probe amplification revealed a duplication of the OPA1 exons 7-9 which was confirmed by long distance PCR and cDNA analysis, resulting in an in-frame duplication of 102 amino acids. Segregation was verified in 53 available members of the updated pedigree and a penetrance of 88% was calculated. Fibroblast cultures from skin biopsies were established to assess the mitochondrial network integrity and to qualitatively and quantitatively study the consequences of the mutation on transcript and protein level. Fibroblast cultures demonstrated a fragmented mitochondrial network. Processing of the OPA1 protein was altered. There was no correlation of the OPA1 transcript levels and the OPA1 protein levels in the fibroblasts. Intriguingly an overall decrease of mitochondrial proteins was observed in patients' fibroblasts, while the OPA1 transcript levels were elevated.ConclusionsThe thorough study of this family provides a detailed clinical picture accompanied by a molecular investigation of patients' fibroblasts. Our data show a classic OPA1-associated non-syndromic ADOA segregating in this family. Cell biological findings suggest that OPA1 is regulated by post-translational mechanisms and we would like to hypothesize that loss of OPA1 function might lead to impaired mitochondrial quality control. With the clinical, genetic and cell biological characterisation of a family described already more than 50 years ago, we span more than half a century of research in optic neuropathies.

Electrophysiological ON and OFF Responses in Autosomal Dominant Optic Atrophy

“…These findings were consistent with the central field defects recorded in ADOA participants in this study and in others. 1,5,44 In addition, whereas the focal PhNRs were both significantly reduced (P < 0.001), only the full-field PhNR OFF was significantly reduced in the full-field ERG (Table 2). Although the N95 and focal PhNR amplitudes were highly discriminatory for ADOA, it should be noted that the participants in this study had relatively late-stage disease.…”

Processing of OPA1 with a novel N-terminal mutation in patients with autosomal dominant optic atrophy: Escape from nonsense-mediated decay

“…Autosomal Dominant Optic Atrophy (ADOA; OMIM: #165500) is the most common form of inherited optic neuropathy leading to progressive bilateral reduction of visual acuity, centrocecal scotomas of variable density, color vision deficits and temporal optic disc pallor, which begin in early childhood [ 1 , 2 ]. Due to variable inter- and intrafamiliar expressivity of ADOA visual impairment may range from mild to severe [ 3 – 5 ].…”

Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics

“…The clinical presentation of DOA is heterogeneous. The ocular phenotype is variable and not all family-members that carry pathogenic mutations in DOA associated genes present visual impairments [ 19 - 21 , 23 - 26 ]. The probability for mutation carriers to develop symptoms during lifetime has been estimated at 88% [ 26 ].…”

“…The ocular phenotype is variable and not all family-members that carry pathogenic mutations in DOA associated genes present visual impairments [ 19 - 21 , 23 - 26 ]. The probability for mutation carriers to develop symptoms during lifetime has been estimated at 88% [ 26 ]. On the other hand, heterozygous OPA1 mutations are associated with a broad range of extra-ocular symptoms, sometimes at the sub-clinical level.…”