LBBMA eOPA1

Autosomal Dominant Optic Atrophy

Autosomal dominant optic atrophy (ADOA), also known as Kjer's disease (OMIM 165500) is characterized by moderate to severe loss of visual acuity with insidious onset in early childhood, blue-yellow dyschromatopsia and central scotoma. There is a considerable inter- and intra-familial variation in visual acuity, and the penetrance may be as low as about 40%. Estimated disease prevalence is between 1:10,000 in Denmark and 1:50,000 worldwide. Histopathological and electrophysiological studies suggest that the underlying defect is retinal ganglion cell degeneration associated with optic atrophy, as observed in Leber’s hereditary optic atrophy (LHON). LHON has a sudden onset of visual loss in both eyes asynchronously and appears at a later age (18-35 yrs), although in atrophic phase is it difficult to distinguish LHON from ADOA without a family history. LHON is maternally transmitted and due to mutations in mitochondrial DNA.

OPA1 gene structure

Click on exons or introns to see relative mutations.

The nomenclature of the mutations described follows the recommendations of the Human Genome Variation Society: http://www.hgvs.org/mutnomen (den Dunnen and Antonarakis, 2000; den Dunnen and Paalman, 2003). Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence. The initiation codon is codon 1. Mutations and NPSVs are described according to OPA1 transcript variant 1 (exon 4/not 4b and 5b; RefSeq: NM_015560.1). If they affect the alternatives exons 4b or 5b, OPA1 transcript variant 8 (exons 4, 4b and 5b; RefSeq: NM_130837.1) is used instead.

Molecular Genetics

Linkage analysis has shown two loci are linked to ADOA phenotype, one on chromosome 3q28 (OPA1), which is the predominant, and one on chromosome 18q12 (OPA4), responsible for the ADOA phenotype. The majority of families are linked to the chromosome 3q28-29 locus. In 2000 two laboratories have found mutations responsible for the disease in a new gene, OPA1, encoding a mitochondrial targeted dynamin-related GTPase (Delettre et al., Nat Genet, 2000, 26:207-210, Alexander et al, Nat Genet, 2000, 26:211-215). The gene comprises 29 exons, 28 of which encode a dynamin-related GTPase of 960 amino acids involved in mitochondrial biogenesis. It has been shown that OPA1 possesses two alternatively spliced additional exons named 4b and 5b, which encode 18 and 37 amino acid sequences.

The OPA1 mutations are spread throughout the gene coding sequence, but most are localized in GTPase domain (exons 8-16) and in the 3’ end of the coding region (exons 27-28), whereas there is a relatively paucity of mutations in exons 1 to 7. Almost 50% of the mutations cause premature truncation of the OPA1 protein. The low detection rate of OPA1 gene mutations in ADOA pedigrees may be a combination of different factors (large-scale mutations as deletions which are not currently tested, mutations in intronic regions and other genes involved in ADOA).

Reference

This work has been published in Human Mutation (Wiley-Liss, Inc.); Digital Object Identifier (DOI): 10.1002/humu.20161

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Revised February 09, 2010
Last major release February 17, 2009