OPA1, the disease gene for optic atrophy type Kjer, is expressed in the inner ear

Abstract

Autosomal dominant optic atrophy (adOA) is the most common form of hereditary optic neuropathy. The majority of cases are associated with mutations in the OPA1 gene. A few cases of adOA are known to be associated with moderate progressive hearing loss. To gain insight into the pathogenesis of this hearing loss, we performed expression analyses of OPA1 in the rat auditory and vestibular organ. In cochlear tissue, several splice variants of OPA1 were detected, which are also expressed in retinal tissue. OPA1 mRNA and protein was found in the hair cells and ganglion cells of the cochlea and vestibular organ. In ganglion cells, OPA1 mRNA and protein was already detectable at birth, whereas in the organ of Corti OPA1 mRNA and protein was up-regulated after birth and reached mature-like expression level during the onset of hearing. Comparison of an antibody directed to the mitochondrial marker protein HSP60 with antibodies directed to different amino acid stretches of OPA1 revealed a sub-cellular distribution of OPA1 in areas of significant density of mitochondria. The data suggest that defects in OPA1 cause hearing disorders due to a progressing metabolic disturbance of hair and ganglion cells in the inner ear.

Vestibular dysfunction in a Japanese patient with a mutation in the gene OPA1

“…In patients having the p.R445H mutation, progressive hearing impairment begins in childhood, and audiological examinations show features of auditory neuropathy, for which the primary lesion is located in the inner hair cells, the auditory nerve, or the synapses between them [4,5]. Recently, a detailed analysis of OPA1 protein expression in the inner ear was reported in rat, and OPA1 protein was detected in the inner hair cells, outer hair cells, and spiral ganglia in the cochlea, as well as the hair cells and ganglia in the vestibular organ [6]. Although there have been several reports of auditory function in patients with this OPA1 mutation, the analysis of vestibular function has not yet been reported in any OPA1 mutation.…”

Mitochondrial Ca2+ uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy

“…Nevertheless, the protein is expressed in all examined human tissues, explaining the accidental development of the so-called 'ADOA +' forms characterized by the association of the blindness with various neuromuscular disorders [17][18][19] or hearing loss [20,21]. The vulnerability of retinal ganglion cells and that of spiral ganglion cells in the inner ear [22] has been attributed to the impairment of ATP production as observed in fibroblasts [23,24] or skeletal muscle [25]. Since retinal ganglion cells are unique among neurons in that the are exposed to direct sunlight, the ensuing oxidative stress may potentiate the consequences of Opa1 dysfunction, leading to apoptosis of these cells [13].…”

The Mitochondrial Connection in Auditory Neuropathy

“…OPA1 is widely expressed in the guinea pig inner ear [Bette et al, 2007] and defects in this protein result in progressive metabolic disturbance of hair cells and SpG cells. In 2 subjects, Huang et al [2009] confirm that AN is associated with DOA but also find unique sensory cell effects like unusually prolonged cochlear microphonic responses to clicks which last for the entire epoch of the ECoG recordings (8 ms) (see fig.…”