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Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease
  1. N J Marchbank1,
  2. J E Craig2,5,
  3. J P Leek1,
  4. M Toohey3,
  5. A J Churchill4,
  6. A F Markham1,
  7. D A Mackey5,
  8. C Toomes1,
  9. C F Inglehearn1
  1. 1Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James’s University Hospital, Leeds LS9 7TF, UK
  2. 2Ophthalmology, Flinders Medical Centre, Adelaide, South Australia, Australia
  3. 3Ballarat Eye Clinic, Marion House, Mair Street, Ballarat, Victoria, Australia
  4. 4Ophthalmology, Bristol Eye Hospital, Lower Maudlin Street, Bristol, UK
  5. 5CERA, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
  1. Correspondence to:
 Dr C Toomes, Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James’s University Hospital, Leeds LS9 7TF, UK;

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Dominant optic atrophy (DOA) is the most common form of autosomally inherited optic neuropathy.1 The disease typically presents in childhood with slow bilateral loss of visual acuity, visual field defects, abnormal colour discrimination, and pallor of the optic discs. The majority of DOA families published to date have shown linkage to a major locus on chromosome 3q28 (OPA1). The OPA1 gene was recently identified and found to encode a ubiquitously expressed, dynamin related GTPase.2,3 In order to determine the mutation spectrum of OPA1 in DOA, we and others have screened the coding exons and their flanking splice sites in large patient cohorts.4–7 Over 60 different mutations have been reported, most of which are specific to individual families. It has been speculated that haploinsufficiency is the cause of disease,3–6 but to date there has been no evidence to prove that this mechanism, rather than aberrant function of mutated proteins, is responsible for the disease.


Using a combined approach of single stranded conformational polymorphism and heteroduplex analysis, we detected mutations in 57% (20/35) of our affected DOA patients.5 Additional DNA samples from an Australian family, in which no OPA1 mutation was identified in the above mutation screen, have recently been obtained enabling further investigation of the cause of disease in this family. All available family members underwent clinical evaluation to determine their disease status. This included best corrected visual acuity (BCVA), assessment of colour vision with Isihara plates and/or City University testing, automated perimetry (Humphrey Field Analyzer, San Leandro, CA), and dilated fundus examination with stereo disc photography. The ocular phenotype observed was typical of DOA with visual acuity reduction ranging from mild to moderate, mild to moderate colour vision disturbance, and visual field analysis ranging from normal to mild paracentral …

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