OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28

Abstract

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

The Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2

“…Mitochondrial transport is essential for neuronal viability 18,19,34,35 . To address whether Alex3 is involved in mitochondrial transport in axons, we used live-imaging techniques.…”

Mitochondrial dynamics in the regulation of neuronal cell death

“…The third GTPase required for mitochondrial fusion is localized to the intermembrane space and is called Opa1 [86][87][88][89]. Opa1 (Optical Atrophy 1) is imported into the mitochondrial inner membrane where it undergoes a regulated cleavage event to release a soluble shorter form of the protein into the intermembrane space.…”

Molecular genetic basis of primary inherited optic neuropathies

“…A gene for dominant optic atrophy mapping to chromosome 3q28-qter, OPA1 36 has been identified. 37,38 A large number of families have been reported to map to the locus on chromosome 3q28-qter, suggesting that it may be the predominant locus. A second dominant optic atrophy locus (OPA4) has been mapped in one pedigree to chromosome 18q12.2-q12, 39 although the gene has not been identified to date.…”