A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect

Abstract

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

“…It has been recently confirmed that OPA1 is involved in the biogenesis and maintenance of mitochondria in mice [Misaka et al, 2002], as well as in humans [Olichon et al, 2002]. Sixty-nine OPA1 gene mutations, mainly family-specific, have been described so far, and the results of these studies support the hypothesis that haploinsufficiency with null mutations and the functional loss of one allele may represent a major mechanism of ADOA [Pesch et al, 2001;Thiselton et al, 2001;Toomes et al, 2001;Delettre et al, 2002;Marchbank et al, 2002]. We report here 14 new OPA1 mutations found in 44 patients with a family history of optic atrophy.…”

The many shapes of mitochondrial death

“…The gene encoding for Opa1 is composed of 30 exons, and at least eight mRNA isoforms arising from alternative splicing and with tissue-specific expression have been identified (Delettre et al, 2001). A total of 83 family-specific mutations have been associated with ADOA so far, and their number seems to be growing (Alexander et al, 2000;Delettre et al, 2000Delettre et al, , 2001Delettre et al, , 2002Pesch et al, 2001;Thiselton et al, 2001Thiselton et al, , 2002Toomes et al, 2001;Marchbank et al, 2002;Shimizu et al, 2002;Amati-Bonneau et al, 2005;Ferre et al, 2005). About half of the mutations associated with the disease are located within the GTPase domain, suggesting that pathogenesis is related to loss of function of the protein and haploinsufficiency in patients with mutation on a single allele (Ferre et al, 2005).…”

Molecular genetic basis of primary inherited optic neuropathies

“…41 There is a wide spectrum of mutations throughout the gene, with over 70 reported to date. 37,38,[41][42][43][44][45][46] There is a concentration of mutations in the GTPase and dynamin central region (coded for by exons 8 to 28), but to date no mutations have been found in exons 4, 4b, and 5b, which are alternately spliced. Since the majority of mutations result in protein truncation, and most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1.…”