1of4 ELECTRONIC LETTER J Med Genet: first published as 10.1136/jmg.2004.025502 on 5 January 2005. Downloaded from A third locus for dominant optic atrophy on chromosome 22q F Barbet, S Hakiki, C Orssaud, S Gerber, I Perrault, S Hanein, D Ducroq, J-L Dufier, A Munnich, J Kaplan, J-M Rozet ............................................................................................................................... J Med Genet 2005;42:e1 (http://www.jmedgenet.com/cgi/content/full/42/1/e1). doi: 10.1136/jmg.2004.025502 utosomal dominant optic atrophy (ADOA) is the most common form of autosomally inherited optic neuro- Key points pathy, with an estimated prevalence of 1:50 000 in A 1 2 most populations, though it can reach 1:10 000 in Denmark. N Autosomal dominant optic atrophies (ADOA) are by The disease typically presents in childhood with variable far the most common mendelian cause of primary bilateral slow visual loss, temporal optic nerve pallor, centro- hereditary optic neuropathy. A major locus has been caecal visual field scotoma, and abnormalities of colour mapped to chromosome 3q28–q29 and the OPA1 vision.3 In most families, the disease is accounted for by gene identified. The penetrance of the disease mutations in the OPA1 gene, at the OPA1 locus on accounted for by mutations in this gene is reported to chromosome 3q28–q29 (MIM165500). The penetrance of be highly variable. A second locus, OPA4, has been the OPA1 disease is highly variable as well as its age of onset, mapped on chromosome 18q12.2–q12.3 in a family even within the same family. whose phenotype was similar to that of OPA1 patients. Some ADOA families have been shown to exclude linkage N to the OPA1 locus.45 In 1999, the genetic study of a large We report the mapping of a third locus of ADOA, family whose phenotype was similar to the OPA1 phenotype, OPA5, on chromosome 22q12.1–q13.1 in two unre- allowed the mapping of a second ADOA locus on chromo- lated families of French origin. The phenotype of some 18q12.2–q12.3 (OPA4, MIM605293).5 To date, no report affected patients of the two families was similar to that has confirmed this localisation and the disease gene is still of patients harbouring OPA1 mutations. unknown. N The OPA5 locus lies in a 10.4 Mb interval flanked by Here we report the mapping of a third ADOA locus on the D22S1148 and D22S283 loci. To date, 73 known chromosome 22q12.1–q13.1 (OPA5) in two unrelated genes and as many predicted genes are contained in families affected with a OPA1-like phenotype. this interval. Screening of OSBP2, C22ORF3, HSC20 and HSPC051 failed to identify any mutation. METHODS Patients http://jmg.bmj.com/ Two unrelated multiplex families of French origin affected with autosomal dominant optic atrophy were ascertained automatic sequencer (ABI 3100, Applied Biosystems, Foster through the genetic consultation clinic of the Hoˆpital des City, California, USA). Linkage analyses were carried out Enfants Malades in Paris (family A and family B; fig 1 A and using M-LINK and LINKMAP of the 5.1 version of the B, respectively). All members of each family underwent Linkage program.78All allele frequencies were available from ophthalmological examination including visual acuity mea- the CEPH database. The gene frequency was estimated to be surements, visual field testing, colour vision analysis, ocular 1/1000 and the penetrance of the disease to be 100%. pressure measurement, examination of the fundi, and on September 26, 2021 by guest. Protected copyright. electrophysiological recordings. Blood was collected from all family members and the DNA was purified by phenol- Screening for mutations in candidate genes chloroform extraction. The 14 exons encoding the oxysterol binding protein 2 (OSBP2), the five hypothetical exons of the chromosome 22 open reading frame 3 (C22ORF3), the six exons of the J Linkage analysis Linkage to known ADOA loci was studied in both families. type co-chaperone HSC20 gene, and the two exons of Four markers flanking the OPA1 locus on chromosome 3q28– the ubiquinol-cytochrome c reductase 7.2 kDa complex q29 were chosen from the Ge´ne´thon linkage map on the basis (HSPC051) were amplified using specific primers designed of their informativeness6—AFM308yf1, AFMa300wa5, from intronic sequences close to the intron-exon junctions AFMb043xe9, and AFM254ve1 at the D3S1601, D3S3590, (not shown, available on request). Amplified products were D3S2748, and D3S1311 loci, respectively. For the OPA4 locus, purified by phenol-chloroform extraction, recovered by we selected three markers lying in the genetic interval on ethanol precipitation, and directly sequenced using the Big chromosome 18q12.2–q12.3 as well as two flanking markers: Dye terminator cycle sequencing kit V3 on a 3100 automated AFM147yf2, AFM191vc7, and AFM284ve1 at the D18S1094, sequencer (ABI Prism, Applied Biosystems). D18S450, and D18S472 loci, respectively; and AFMa224wb1 and AFM295xh1 at the D18S1102 and D18S474 loci. RESULTS A 10 cM genome-wide search for the disease causing gene Clinical evaluation was undertaken in family A using fluorescent oligonucleo- We report two unrelated multiplex families of French origin tides flanking the 382 polymorphic markers of the Genescan affected with ADOA. Although the age of onset of the disease Linkage Mapping Set, version II (Perkin Elmer Cetus), under conditions recommended by the manufacturer. Amplified fragments were electrophoresed and analysed on an Abbreviations: ADOA, autosomal dominant optic atrophy www.jmedgenet.com 2of4 Barbet, Hakiki, Orssaud, et al J Med Genet: first published as 10.1136/jmg.2004.025502 on 5 January 2005. Downloaded from Family A Family B I I 1 2 1 2 D22S420 12 8 4 D22S315 2 5 1 D22S1148 8 10 7 D22S1154 5 2 2 D22S1167 4 6 4 II D22S1144 6 4 4 1 2 3 4 5 6 7 8 D22S1163 2 2 4 D22S275 3 8 9 D22S420 4 2 4 2 2 2 4 2 4 4 4 2 5 3 4 2 D22S1150 2 2 3 D22S315 1 1 2 1 1 1 2 1 2 2 1 1 4 9 1 1 D22S1176 3 4 2 D22S1148 11 1 12 1 2 1 12 1 1 1 11 1 1 1 11 1 D22S273 1 2 5 D22S1154 2 5 2 5 2 2 2 5 2 5 2 5 2 2 2 5 D22S280 5 1 7 D22S1167 1 2 2 4 4 4 2 2 2 2 1 2 5 1 2 4 D22S281 1 6 6 D22S1144 7 1 7 1 4 4 7 1 4 1 7 1 3 7 7 1 D22S1158 8 14 8 D22S1163 2 2 4 2 4 2 4 2 1 2 2 2 4 4 4 2 D22S1147 1 5 1 D22S275 8 4 1 1 4 1 1 4 4 4 8 4 1 2 1 1 D22S278 6 2 2 D22S1150 10 2 3 3 2 3 3 2 2 2 10 2 11 3 3 3 D22S283 8 13 15 D22S1176 3 2 4 1 1 3 4 2 5 8 3 2 1 2 4 1 D22S1177 4 5 1 D22S273 1 1 2 2 2 1 2 1 3 1 1 1 2 6 2 2 D22S1156 2 2 2 D22S280 2 1 5 1 7 4 5 1 3 2 2 1 2 4 5 1 D22S281 2 3 3 3 9 5 3 3 6 5 2 3 10 5 3 3 D22S1158 2 10 4 9 10 2 4 10 2 2 2 10 12 2 4 9 D22S1147 1 8 1 1 1 1 1 8 5 1 1 8 2 1 1 1 II D22S278 5 2 4 6 2 2 4 6 2 4 5 2 5 2 4 6 1 2 3 4 D22S283 8 8 8 15 15 3 8 15 1 13 1 8 6 1 8 15 D22S420 2 4 2 8 2 8 2 5 D22S1177 3 1 3 1 1 5 3 1 1 4 2 1 5 4 3 1 D22S315 11 1 2 5 2 5 12 1 D22S1156 2 2 2 6 2 2 2 6 1 6 1 2 2 2 2 6 D22S1148 2 2 8 10 8 10 1 2 D22S1154 2 2 5 2 5 2 3 2 D22S1167 1 2 4 6 4 6 2 2 III D22S1144 4 1 6 4 6 4 1 5 1 2 3 4 5 D22S1163 4 4 2 2 2 2 2 2 D22S275 2 4 3 8 3 8 5 5 D22S420 2 2 4 4 4 4 5 4 5 4 D22S1150 3 2 2 2 2 2 3 3 D22S315 2 1 2 2 2 2 4 1 4 1 D22S1176 1 3 3 4 3 4 3 1 D22S1148 12 2 12 1 12 1 1 11 1 11 D22S273 2 1 1 2 1 2 4 2 D22S1154 2 2 2 2 2 2 2 2 2 2 D22S280 4 1 5 1 5 1 2 4 D22S1167 2 4 2 2 2 2 5 2 5 2 D22S281 5 2 1 6 1 6 1 6 D22S1144 7 4 7 4 7 4 3 7 3 7 D22S1158 5 14 8 14 8 8 8 8 D22S1163 4 4 4 1 4 1 4 4 4 4 D22S1147 6 1 1 5 1 1 1 1 D22S275 1 4 1 4 1 4 1 1 1 1 D22S278 2 4 6 2 6 2 6 2 D22S1150 3 2 3 2 3 2 11 3 11 3 D22S283 12 16 8 13 8 15 8 1 D22S1176 4 1 4 5 4 5 1 4 1 4 D22S1177 3 1 4 5 4 1 4 1 D22S273 2 2 2 3 2 3 2 2 2 2 D22S1156 2 2 2 2 2 2 7 2 D22S280 5 7 5 3 5 3 2 5 2 5 D22S281 3 9 3 6 3 6 10 3 10 3 D22S1158 4 10 4 2 4 2 12 4 12 4 D22S1147 1 1 1 5 1 5 2 1 2 1 III D22S278 4 2 4 2 4 2 5 4 5 4 1 2 3 D22S283 8 15 8 1 8 1 6 8 6 8 D22S420 2 8 2 8 8 2 D22S1177 3 1 3 1 3 1 5 3 5 3 D22S315 11 5 1 2 5 12 D22S1156 2 2 2 1 2 1 2 2 2 6 D22S1148 2 10 2 8 10 1 D22S1154 2 2 2 5 2 3 D22S1167 1 6 2 4 6 2 D22S1144 4 4 1 6 4 1 http://jmg.bmj.com/ D22S1163 4 2 4 2 2 2 D22S275 2 8 4 3 8 5 D22S1150 3 2 2 2 2 3 D22S1176 1 4 3 3 4 3 D22S273 2 2 1 1 2 4 D22S280 4 1 1 5 1 2 D22S281 5 6 2 1 6 1 D22S1158 5 14 14 8 8 8 D22S1147 6 5 1 1 1 1 Figure 1 Haplotype of families A and B at the OPA5 locus on D22S278 2 2 4 6 2 6 D22S283 12 13 16 8 15 8 chromosome 22q12.1–q13.1, respectively.