Dominant optic atrophy: correlation between clinical and molecular genetic studies

Abstract

ABSTRACT.Purpose: To assess the clinical picture and molecular genetics of 14 Finnish families with dominant optic atrophy (DOA). Methods: The clinical status of family members was based on the assessment of visual acuity, colour vision, visual fields and optic nerve appearance; 31 individuals were affected, two suspect and 21 unaffected. A total of 30 coding exons and exonÀ intron boundaries of the OPA1 gene were sequenced in order to detect mutations. Results: Half the patients were diagnosed at the age of £20 years. Ten out of 20 affected individuals followed up for ‡6 years had a progressive disease and 10 had a stable disease. According to WHO criteria, 36% of the affected patients were visually handicapped. Eight OPA1 pathogenic mutations, all but one novel, and 18 neutral polymorphisms were detected. Conclusion: The most sensitive indicators of DOA were optic disc pallor and dyschromatopsia. With molecular genetic analysis, asymptomatic mutation carriers and DOA cases with a mild clinical outcome were ascertained. No mutational hotspot or Finnish major mutation in the OPA1 gene could be demonstrated as most families carried a unique mutation. No obvious genotypeÀ phenotype correlation could be detected. Detailed clinical assessment and exclusion of non-DOA families prior to mutation screening are necessary for obtaining a high mutation detection rate.

OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy

“…15 Because the majority of OPA1 mutations truncate or disrupt the normal gene product and thus represent null alleles, haploinsufficiency has been cited as the major mechanism of action. 2,3,16 However, there are a number of pathogenic missense mutations and an example of semi-dominant inheritance in an OPA1 compound heterozygote, suggesting that different pathways of altered OPA1 protein function or production can lead to ADOA. 2,15,16 OPA1 mutations account for roughly one-third to twothirds of ADOA cases, and this locus heterogeneity may be responsible for the considerable phenotypic heterogeneity seen in ADOA.…”

“…3 Although a deleterious mutation can occur throughout the gene, Thistleton et al (2002) have identified three general regions where mutations have loosely clustered: the N-terminal leader sequence (exons 1-2) domain, the GTPase (exons [8][9][10][11][12][13][14][15][16] domain, and the C-terminus (exons [27][28]. 15 Because the majority of OPA1 mutations truncate or disrupt the normal gene product and thus represent null alleles, haploinsufficiency has been cited as the major mechanism of action.…”

“…ADOA is clinically characterized by loss of visual acuity, central visual field defects, color vision abnormalities, and optic nerve pallor. [1][2][3] Disease progression is typically slow and the age of onset is frequently in childhood, although it can vary significantly. 3 Neuropathologically, ADOA shares end-stage features, including retinal ganglion cell death and optic nerve atrophy, with the primary mitochondrial optic neuropathy, Leber's Hereditary Optic Neuropathy (LHON), a disorder caused by point mutations in the mitochondrial DNA (mtDNA).…”

“…2,15,16 OPA1 mutations account for roughly one-third to twothirds of ADOA cases, and this locus heterogeneity may be responsible for the considerable phenotypic heterogeneity seen in ADOA. 3,5,15,16 Other genetic loci associated with Mendelian inherited optic atrophy have been mapped including two additional autosomal dominant (OPA4 and OPA5), a variable form that can be recessive or dominant with cataracts (OPA3), and an X-linked (OPA2) optic atrophy locus. [17][18][19] However, incomplete penetrance and variable expressivity is common even within ADOA families.…”

“…2,3 The OPA1 gene encodes a 960-amino acid dynaminlike GTPase protein consisting of an N-terminal mitochondrial leader sequence, a highly conserved GTPase (exons 8 -16) domain, and a C-terminal coiled-coil (including exons 27 and 28) motif. 4 -6 It is ubiquitously expressed in the body, with highest expression in the retina and brain.…”