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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 307521.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy
Authors:Dadgar, Sharareh; Hagens, Olivier; Dadgar, Seyed Razi; Haghighi, Ehsan Nobakht; Schimpf, Simone; Wissinger, Bernd; Garshasbi, Masoud
Date of Publication (YYYY-MM-DD):2006-05-12
Title of Journal:Experimental Eye Research
Journal Abbrev.:Exp. Eye Res
Issue / Number:3
Start Page:702
End Page:706
Copyright:© 2006 Elsevier Ltd All rights reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description: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 14–15 years. 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.
Free Keywords:optic atrophy; OPA1; homology modeling; dynamin A
Comment of the Author/Creator:Corresponding author. Tel.: +49 30 8413 1244; fax.: +49 30 8413 1383.
Present address: Banting and Best Department of Medical Research, University of Toronto, 112 College Street, Toronto, Ontario, Canada M5G 1L6.
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Faculty of Medicine, Iran University of Medical Sciences, P.O. Box 14155/5983, Tehran, Iran;
2.Clinical Skill Lab Center, Iran University of Medical Sciences, Firoozgar Hospital, 15900 Tehran, Iran;
3.Molecular Genetics Laboratory, University Eye Hospital, University of Tuebingen, Roentgenweg 11, D-72076 Tuebingen, Germany .
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