Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy.

Abstract

Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14-15years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2-q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.

• Authors: Sharareh Dadgar, Olivier Hagens, Seyed Razi Dadgar, Ehsan Nobakht Haghighi, Simone Schimpf, Bernd Wissinger, Masoud Garshasbi
• Journal: Experimental eye research (Exp Eye Res) Vol. 83 Issue 3 Pg. 702-6 (Sep 2006) ISSN: 0014-4835 [Print] England
• PMID: 16698014 (Publication Type: Letter, Research Support, Non-U.S. Gov't)

Chemical References

• GTP Phosphohydrolases
• OPA1 protein, human

Topics

• Adolescent
• Animals
• GTP Phosphohydrolases (genetics)
• Humans
• Models, Molecular
• Mutation, Missense
• Optic Atrophy, Autosomal Dominant (genetics)
• Protein Structure, Tertiary
• Sequence Homology