Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1.
OBJECTIVE
To describe the clinical features of and identify the disease-causing mutation in a large Utah family segregating a dominantly inherited syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia.


METHODS
Observational case series.


METHODS
Thirty individuals at risk for a syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia in a single family underwent clinical examinations and venipuncture. Linkage analysis and mutation screening of the optic atrophy 1 gene (OPA1) were performed.


RESULTS
Eighteen individuals demonstrated characteristics of the syndrome. Genetic analysis identified a G-->A substitution at nucleotide position 1334 in exon 14 of OPA1 causing an arginine-to-histidine change (R445H) in all affected members of the family. This change segregated with the disease phenotype in the study family with a LOD score of 7.02 at theta; = 0 and was not found in 200 normal control subjects. Analysis of an unrelated Belgian family with a similar phenotype revealed the same R445H mutation segregating with the disease phenotype.


CONCLUSIONS
This study describes a mutation in OPA1 causing a unique syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia. These results expand the spectrum of human disease associated with mutations of OPA1 and indicate that ophthalmologists caring for patients with optic atrophy should inquire about possible associated hearing loss. Although OPA1 is a nuclear gene, the gene product localizes to mitochondria, suggesting that mitochondrial dysfunction may be the final common pathway for many forms of syndromic and nonsyndromic optic atrophy, hearing loss, and external ophthalmoplegia.
Payne
Marielle
M
Department of Ophthalmology and Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
Yang
Zhenglin
Z
Katz
Bradley J
BJ
Warner
Judith E A
JE
Weight
Christopher J
CJ
Zhao
Yu
Y
Pearson
Erik D
ED
Treft
Robert L
RL
Hillman
Todd
T
Kennedy
Richard J
RJ
Meire
Francoise M
FM
Zhang
Kang
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D001763:Blepharoptosis / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009886:Ophthalmoplegia / Q000235:genetics*; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome
D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human