A high-density transcript map of the human dominant optic atrophy OPA1 gene locus and re-evaluation of evidence for a founder haplotype

Abstract

Dominant optic atrophy (DOA, gene OPA1) is the commonest form of inherited optic atrophy. Linkage studies have shown that a locus for this disease lies in a 1.4-cM region at chromosome 3q28→q29 and have suggested a founder haplotype for as many as 95% of the linked families. To aid the identification of candidate genes for this disease, we have constructed a Bacterial Artificial Chromosome (BAC) contig covering approximately 3.3 Mb and encompassing the OPA1 critical region (flanking markers D3S3669 and D3S3562). This physical map corrects errors in the marker order reported in the literature, allowing the OPA1 critical region to be precisely defined. A reassessment of the founder effect in the light of the revised marker order suggests that it may not be as significant as had previously been suggested. A high-density transcript map was created by precisely mapping genes and expressed sequence tags (ESTs) from GeneMap’99, that have been loosely assigned to the region by radiation hybrid mapping. One known gene (KIAA0567 protein) and 15 ESTs were found to lie within the minimal disease region. Analysis of the sequence data already available from within the OPA1 critical region allowed the identification and mapping of a further 31 ESTs. The work presented in this study provides the basis for the characterisation of candidate genes and the ultimate identification of the gene mutated in DOA.

Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease

“…We performed genotyping on genomic DNA from all available family members, using 12 microsatellite markers surrounding the OPA1 gene (fig 1, method described previously 8 ). On first examination of the data, three of the markers (D3S1523, D3S3590, and D3S2305) appeared to be homozygous in every affected subject.…”

“…The size of the deletion in this family was estimated at 560-860 kb based on the physical distance between the microsatellite markers on our physical map. 8 Small interstitial deletions are often the result of rearrangements in regions of the genome containing low copy number repeat units (LCNRs) that promote unequal crossing over. 13 These types of repeat sequences have been found flanking the deletion breakpoints in a number of diseases such as Williams syndrome 14 and DiGeorge/velocardiofacial syndrome.…”

“…17 Indeed, we have previously mapped numerous expressed sequence tags derived from as yet unknown genes to this region. 8 Since the deletion encompasses other genes in the 3q28 region, it was of particular interest to note the presence of pes cavus (high foot arch) and reduced deep tendon reflexes in an older affected subject (I.1) and of "toe-walking" in two younger subjects (III.4 and III.7). The possibility of either additional systemic manifestations of DOA hitherto unreported, or the presence of a contiguous gene syndrome owing to deletion of adjacent genes led us to investigate this family further.…”

OPA1 analysis in an international series of probands with bilateral optic atrophy

“…Altogether, 16 probands of 39 did not report a family history of visual loss, and in five probands this (Delettre et al 2000(Delettre et al , 2001Murton et al 2001;Pesch et al 2001;Toomes et al 2001; Baris et al 2003;Schimpf et al 2008) 34 (Delettre et al 2000(Delettre et al , 2001Murton et al 2001;Pesch et al 2001;Toomes et al 2001; Baris et al 2003;Schimpf et al 2008) 40 NM_130837.2 was used as the reference sequence. Chromosomal position corresponds to the human genome build GRCh37/hg19 and in case of a deletion or duplication of multiple nucleotides the position of the first nucleotide is indicated.…”

“…Altogether, 16 probands of 39 did not report a family history of visual loss, and in five probands this (Delettre et al 2000(Delettre et al , 2001Murton et al 2001;Pesch et al 2001;Toomes et al 2001;Baris et al 2003;Schimpf et al 2008) 34 information was not available. Mutational screening and clinical evaluation to assess possible de novo occurrence and penetrance could be performed (due to sample unavailability) only in two-first degree relatives from pedigrees of probands 8 and 14.…”