Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): Identification of the OPA3 gene and its founder mutation in Iraqi Jews

Type III 3-methylglutaconic aciduria (MGA) (MIM 258501) is a neuro-ophthalm ologic syndrome that consists of early-onset bilateral optic atrophy and la ter-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Ur inary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased. The disorder has been reported in 40 patients of Iraqi Jewish or igin, allowing the mapping of the disease to chromosome 19q13.2-q13.3, by l inkage analysis. To isolate the causative gene, OPA3, we sequenced four gen es within the critical interval and identified, in the intronic sequence of a gene corresponding to cDNA clone FLJ22187, a point mutation that segrega ted with the type III MGA phenotype. The FLJ22187-cDNA clone, which we iden tified as the OPA3 gene, consists of two exons and encodes a peptide of 179 amino acid residues. Northern blot analysis revealed a primary transcript of similar to5.0 kb that was ubiquitously expressed, most prominently in sk eletal muscle and kidney. Within the brain, the cerebral cortex, the medull a, the cerebellum, and the frontal lobe, compared to other parts of the bra in, had slightly increased expression. The intronic G -->C mutation abolish ed mRNA expression in fibroblasts from affected patients and was detected i n 8 of 85 anonymous Israeli individuals of Iraqi Jewish origin. Milder muta tions in OPA3 should be sought in patients with optic atrophy with later on set, even in the absence of additional neurological abnormalities.