Dominant Optic Atrophy, Sensorineural Hearing Loss, Ptosis, and Ophthalmoplegia: A Syndrome Caused by a Mutation in OPA1

Abstract

Abstract: : Purpose:A three–generation Utah family with a syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia transmitted in an autosomal dominant pattern was identified. A few syndromes involving both optic atrophy and hearing loss have been described, but no non–mitochondrial gene has yet been identified to cause both deficits. We perfomed clinical and genetic study in an extensive multiple–generation Utah family with a syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia. Methods:Ophthalmologic examinations were performed, and genomic DNA was extracted from blood samples after informed consents were obtained. DNA samples were amplified by the polymerase chain reaction and genotyped with polymorphic DNA markers encompassing the OPA1 gene on a Beckman–Coulter CEQ 8000 Genetic Analysis System. The employed microsatellite markers included D3S1311, D3S2418, D3S2305 and D3S3590. Direct DNA sequencing was conducted to identify mutations in the OPA1 gene. Results: Linkage analysis with short tandem repeat polymorphic markers revealed positive linkage to 3q28–29 with a LOD score of 5.16 at &#952=0 with marker D3S3590. Sequence analysis of the OPA1 gene revealed a missense mutation of G–to–A causing an arginine to histidine change at codon 445 in exon 14. The change segregated within the family and was not found in 200 normal individuals Conclusions: We have identified a mutation in the OPA1 gene already shown to cause an autosomal dominant form of optic atrophy causing a syndrome of optic atrophy, sensorineural hearing loss, ptosis and ophthalmoplegia. Our results expand the spectrum of the OPA1 gene in human disease. Identification of this mutation allows for molecular diagnosis and will hopefully lead to better understanding and treatment of this rare genetic disorder

Keywords: genetics • neuro–ophthalmology: optic nerve • gene screening