OPA1 (Kjer Type) Dominant Optic Atrophy: A Novel Mitochondrial Disease

3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings

“…Mitochondrial defects can also present with optic atrophy. A dominant form of optic atrophy (Kjer type) is the most common inherited optic neuropathy, and the responsible gene, OPA1, encodes a mitochondrial dynamin-related GTPase [10]. Leber's hereditary optic neuropathy constitutes another example of mitochondrial involvement in a disorder manifesting optic atrophy [11].…”

The many shapes of mitochondrial death

“…The gene encoding for Opa1 is composed of 30 exons, and at least eight mRNA isoforms arising from alternative splicing and with tissue-specific expression have been identified (Delettre et al, 2001). A total of 83 family-specific mutations have been associated with ADOA so far, and their number seems to be growing (Alexander et al, 2000;Delettre et al, 2000Delettre et al, , 2001Delettre et al, , 2002Pesch et al, 2001;Thiselton et al, 2001Thiselton et al, , 2002Toomes et al, 2001;Marchbank et al, 2002;Shimizu et al, 2002;Amati-Bonneau et al, 2005;Ferre et al, 2005). About half of the mutations associated with the disease are located within the GTPase domain, suggesting that pathogenesis is related to loss of function of the protein and haploinsufficiency in patients with mutation on a single allele (Ferre et al, 2005).…”

Hereditary optic neuropathies

“…100,101,[120][121][122][123][124][125] Between 30 and 90% of these families have been found to harbour over 60 different missence and nonsense mutations, deletions, and insertions in a gene within this region that has been designated the OPA1 gene. [122][123][124][125][126][127][128] The product of the OPA1 gene is targeted to the mitochondria and appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. [122][123][124] Downregulation of the OPA1 leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential with cytochorme c release and caspase-dependent apoptosis.…”

“…[122][123][124][125][126][127][128] The product of the OPA1 gene is targeted to the mitochondria and appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity. [122][123][124] Downregulation of the OPA1 leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential with cytochorme c release and caspase-dependent apoptosis. 129 These findings demonstrate the crucial role of mitochondria in retinal ganglion cell pathophysiology.…”

“…129 These findings demonstrate the crucial role of mitochondria in retinal ganglion cell pathophysiology. 124 Linkage analysis of patients with normal tension glaucoma has shown an association with polymorphisms of the OPA1 gene. 130 Interestingly, there is a mutant strain of mice with dominantly inherited optic atrophy with variable expressivity.…”