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A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy

Thiselton, DL; Alexander, C; Taanman, JW; Brooks, S; Rosenberg, T; Eiberg, H; Andréasson, Sten LU ; Van Regemorter, N; Munier, FL and Moore, AT, et al. (2002) In Investigative Ophthalmology & Visual Science 43(6). p.1715-1724
Abstract
PURPOSE. To characterize the spectrum of mutations in the OPA1 gene in a large international panel of patients with autosomal dominant optic atrophy (adOA), to improve understanding of the range of functional deficits attributable to sequence variants in this gene, and to assess any genotype-phenotype correlations. METHODS. All 28 coding exons of OPA1, intron-exon splice sites, 273 bp 5' to exon 1, and two intronic regions with putative function were screened in 94 apparently unrelated white patients of European origin with adOA by single-strand conformational polymorphism (SSCP)-heteroduplex analysis and direct sequencing. Clinical data were collated, and putative mutations were tested for segregation in the respective families by SSCP... (More)
PURPOSE. To characterize the spectrum of mutations in the OPA1 gene in a large international panel of patients with autosomal dominant optic atrophy (adOA), to improve understanding of the range of functional deficits attributable to sequence variants in this gene, and to assess any genotype-phenotype correlations. METHODS. All 28 coding exons of OPA1, intron-exon splice sites, 273 bp 5' to exon 1, and two intronic regions with putative function were screened in 94 apparently unrelated white patients of European origin with adOA by single-strand conformational polymorphism (SSCP)-heteroduplex analysis and direct sequencing. Clinical data were collated, and putative mutations were tested for segregation in the respective families by SSCP analysis or direct sequencing and in 100 control chromosomes. Further characterization of selected splice site mutations was performed by RT-PCR of patient leukocyte RNA. Staining of mitochondria in leukocytes of patients and control subjects was undertaken to assess gross differences in morphology and cellular distribution. RESULTS. Twenty different mutations were detected, of which 14 were novel disease mutations (missense, nonsense, deletion-frameshift, and splice site alterations) and six were known mutations. Mutations were found in 44 (47%) of the 94 families, included in the study. Ten new polymorphisms in the OPA1 gene were also identified. Mutations occur throughout the gene, with three clusters emerging: in the mitochondrial leader, in the highly conserved guanosine triphosphate (GTP)-binding domain, and in the -COOH terminus. Examination of leukocyte mitochondria from two unrelated patients with splice site mutations in OPA1 revealed no abnormalities of morphology or cellular distribution when compared with control individuals. CONCLUSIONS. This study describes 14 novel mutations in the OPA1 gene in patients with adOA, bringing the total number so far reported to 54. It is likely that many cases of adOA are due to mutations outside the coding region of OPA1 or to large-scale rearrangements. Evaluation of the mutation spectrum indicates more than one pathophysiological mechanism for adOA. Preliminary data suggests that phenotype-genotype correlation is complex, implying a role for other genetic modifying or environmental factors. No evidence was found of pathologic changes in leukocyte mitochondria of patients with adOA. (Less)
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published
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Investigative Ophthalmology & Visual Science
volume
43
issue
6
pages
1715 - 1724
publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
external identifiers
  • pmid:12036970
  • wos:000175927800005
  • scopus:0036268633
ISSN
1552-5783
language
English
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yes
id
48caaf7c-d91a-4214-95e0-b8d3e521ee5f (old id 336268)
alternative location
http://www.iovs.org/cgi/content/abstract/43/6/1715
date added to LUP
2007-11-15 14:27:10
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2017-10-22 04:42:25
@article{48caaf7c-d91a-4214-95e0-b8d3e521ee5f,
  abstract     = {PURPOSE. To characterize the spectrum of mutations in the OPA1 gene in a large international panel of patients with autosomal dominant optic atrophy (adOA), to improve understanding of the range of functional deficits attributable to sequence variants in this gene, and to assess any genotype-phenotype correlations. METHODS. All 28 coding exons of OPA1, intron-exon splice sites, 273 bp 5' to exon 1, and two intronic regions with putative function were screened in 94 apparently unrelated white patients of European origin with adOA by single-strand conformational polymorphism (SSCP)-heteroduplex analysis and direct sequencing. Clinical data were collated, and putative mutations were tested for segregation in the respective families by SSCP analysis or direct sequencing and in 100 control chromosomes. Further characterization of selected splice site mutations was performed by RT-PCR of patient leukocyte RNA. Staining of mitochondria in leukocytes of patients and control subjects was undertaken to assess gross differences in morphology and cellular distribution. RESULTS. Twenty different mutations were detected, of which 14 were novel disease mutations (missense, nonsense, deletion-frameshift, and splice site alterations) and six were known mutations. Mutations were found in 44 (47%) of the 94 families, included in the study. Ten new polymorphisms in the OPA1 gene were also identified. Mutations occur throughout the gene, with three clusters emerging: in the mitochondrial leader, in the highly conserved guanosine triphosphate (GTP)-binding domain, and in the -COOH terminus. Examination of leukocyte mitochondria from two unrelated patients with splice site mutations in OPA1 revealed no abnormalities of morphology or cellular distribution when compared with control individuals. CONCLUSIONS. This study describes 14 novel mutations in the OPA1 gene in patients with adOA, bringing the total number so far reported to 54. It is likely that many cases of adOA are due to mutations outside the coding region of OPA1 or to large-scale rearrangements. Evaluation of the mutation spectrum indicates more than one pathophysiological mechanism for adOA. Preliminary data suggests that phenotype-genotype correlation is complex, implying a role for other genetic modifying or environmental factors. No evidence was found of pathologic changes in leukocyte mitochondria of patients with adOA.},
  author       = {Thiselton, DL and Alexander, C and Taanman, JW and Brooks, S and Rosenberg, T and Eiberg, H and Andréasson, Sten and Van Regemorter, N and Munier, FL and Moore, AT and Bhattacharya, SS and Votruba, M},
  issn         = {1552-5783},
  language     = {eng},
  number       = {6},
  pages        = {1715--1724},
  publisher    = {ASSOC RESEARCH VISION OPHTHALMOLOGY INC},
  series       = {Investigative Ophthalmology & Visual Science},
  title        = {A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy},
  volume       = {43},
  year         = {2002},
}