OPA1: 516 unique variants and 831 patients registered in an updated centralized Variome database

Abstract

Background The dysfunction of OPA1, a dynamin GTPase involved in mitochondrial fusion, is responsible for a large spectrum of neurological disorders, each of which includes optic neuropathy. The database dedicated to OPA1 ( https://www.lovd.nl/OPA1 ), created in 2005, has now evolved towards a centralized and more reliable database using the Global Variome shared Leiden Open-source Variation Database (LOVD) installation. Results The updated OPA1 database, which registers all the patients from our center as well as those reported in the literature, now covers a total of 831 patients: 697 with isolated dominant optic atrophy (DOA), 47 with DOA “plus”, and 83 with asymptomatic or unclassified DOA. It comprises 516 unique OPA1 variants, of which more than 80% (414) are considered pathogenic. Full clinical data for 118 patients are documented using the Human Phenotype Ontology, a standard vocabulary for referencing phenotypic abnormalities. Contributors may now make online submissions of phenotypes related to OPA1 mutations, giving clinical and molecular descriptions together with detailed ophthalmological and neurological data, according to an international thesaurus. Conclusions The evolution of the OPA1 database towards the LOVD, using unified nomenclature, should ensure its interoperability with other databases and prove useful for molecular diagnoses based on gene-panel sequencing, large-scale mutation statistics, and genotype-phenotype correlations.

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

“…Dominant optic atrophy (DOA, MIM*605290) is the most commonly inherited optic neuropathy, leading to irreversible loss of retinal ganglion cells (RGCs), optic nerve degeneration, and central visual loss. 1,2 More than 400 OPA1 variants were identified in DOA individuals, [3][4][5][6] resulting in excess of mitochondrial fission. 7,8 Surprisingly, a similar clinical presentation was also reported in individuals with dominant DNM1L mutations 9 (MIM603850) and mitochondrial network hyperfusion, thus providing evidence that alterations of both fusion and fission compromise RGC survival.…”

Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy

“…In dominant optic atrophy (DOA, MIM165500), it is now well established that mutations in genes involved in mitochondrial dynamics such as OPA1 (MIM#605290) are the main cause of the disease. More than 400 distinct pathogenic variants have been described in OPA1 [ 3 – 6 ], affecting the pro-fusion activity of this large dynamin-related GTPase resulting in defective mitochondrial fusion [ 7 , 8 ]. The implication of mitochondrial dynamics in DOA was further supported by the identification of dominant mutations in MFN2 (MIM#608507) [ 9 ] and OPA3 (MIM#606580) [ 10 ], two additional genes acting on mitochondrial dynamics.…”

Hereditary Optic Neuropathies: Induced Pluripotent Stem Cell-Based 2D/3D Approaches

“…To date, more than 400 OPA1 pathogenic variants have been reported of which, 28% are missense variations, 24% are associated with altered splicing, 22% are frameshift variants, 15% are nonsense variants and 7% are deletions. Conversely, the majority of the variants result in a truncated protein, supporting haploinsufficiency as the main pathological mechanism of the disease [ 39 ]. Due to this fact, mitochondria become disarranged, and, finally, the energy production capacity is diminished.…”