All the causative
OPA1 mutations in these “DOA plus” families have so far been missense mutations with most, but not all of them, within the catalytic GTPase site of the protein.
4 5 6 Although functional studies are lacking, it has been speculated that the more severe phenotype is the consequence of the mutant Opa1 protein exerting a dominant negative effect, and the more severe cellular dysfunction becomes apparent not only within RGCs, but also in other “at-risk mitochondrial” tissues such as extra-ocular muscles, skeletal muscle, and brain.
27 If this hypothesis is substantiated, it is perhaps not surprising that we failed to detect these abnormalities in our
Opa1 mutant mice, where the pathology is limited to the optic nerve, that is, “pure DOA,” with no evidence to suggest additional neurologic deficits such as muscle weakness, ataxia, or deafness, using the well-validated primary SHIRPA screen.
11 The heterozygous exon 8 mutation (c.1051C>T) in our
Opa1 mice is also truncative (Q285STOP) and overall results in a 50% reduction in the expression of the Opa1 protein, thereby representing a haploinsufficiency, and not a dominant negative, disease model. We previously showed the following percentage decrease in Opa1 protein levels in a panel of post-mitotic tissues harvested from
Opa1 +/− mice: retina (55%), brain (50%), skeletal muscle (80%), heart (55%), liver (80%), kidney (35%), and spleen (65%).
8