OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance
- PMID: 11440988
- DOI: 10.1093/hmg/10.13.1359
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance
Abstract
We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28-q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.
Similar articles
-
A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy.Invest Ophthalmol Vis Sci. 2002 Jun;43(6):1715-24. Invest Ophthalmol Vis Sci. 2002. PMID: 12036970
-
OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.Nat Genet. 2000 Oct;26(2):211-5. doi: 10.1038/79944. Nat Genet. 2000. PMID: 11017080
-
Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.Hum Mol Genet. 2001 Jun 15;10(13):1369-78. doi: 10.1093/hmg/10.13.1369. Hum Mol Genet. 2001. PMID: 11440989
-
Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1.Mol Med Rep. 2016 Jul;14(1):33-40. doi: 10.3892/mmr.2016.5209. Epub 2016 May 4. Mol Med Rep. 2016. PMID: 27150940 Free PMC article. Review.
-
OPA1-associated disorders: phenotypes and pathophysiology.Int J Biochem Cell Biol. 2009 Oct;41(10):1855-65. doi: 10.1016/j.biocel.2009.04.012. Epub 2009 Apr 21. Int J Biochem Cell Biol. 2009. PMID: 19389487 Review.
Cited by
-
OPA1, a molecular regulator of dilated cardiomyopathy.J Cell Mol Med. 2023 Oct;27(20):3017-3025. doi: 10.1111/jcmm.17918. Epub 2023 Aug 21. J Cell Mol Med. 2023. PMID: 37603376 Free PMC article. Review.
-
Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy.BMC Med Genet. 2011 Apr 4;12:49. doi: 10.1186/1471-2350-12-49. BMC Med Genet. 2011. PMID: 21457585 Free PMC article.
-
Gene structure and chromosomal localization of mouse Opa1 : its exclusion from the Bst locus.BMC Genet. 2003 May 7;4:8. doi: 10.1186/1471-2156-4-8. BMC Genet. 2003. PMID: 12735796 Free PMC article.
-
Mutations at a split codon in the GTPase-encoding domain of OPA1 cause dominant optic atrophy through different molecular mechanisms.Hum Mol Genet. 2022 Mar 3;31(5):761-774. doi: 10.1093/hmg/ddab286. Hum Mol Genet. 2022. PMID: 34559197 Free PMC article.
-
[How to distinguish between autosomal dominant optic atrophy and Leber's hereditary optic neuropathy].Ophthalmologe. 2007 Dec;104(12):1060-5. doi: 10.1007/s00347-007-1577-y. Ophthalmologe. 2007. PMID: 17899121 German.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases