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
-
Exome sequencing identified a novel de novo OPA1 mutation in a consanguineous family presenting with optic atrophy.Genet Res (Camb). 2016 Jun 6;98:e10. doi: 10.1017/S0016672316000070. Genet Res (Camb). 2016. PMID: 27265430 Free PMC article.
-
High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.EMBO Mol Med. 2021 Jun 7;13(6):e13579. doi: 10.15252/emmm.202013579. Epub 2021 May 20. EMBO Mol Med. 2021. PMID: 34014035 Free PMC article.
-
Activation of cryptic splice sites is a frequent splicing defect mechanism caused by mutations in exon and intron sequences of the OPA1 gene.Hum Genet. 2006 Feb;118(6):767-71. doi: 10.1007/s00439-005-0096-7. Epub 2005 Dec 2. Hum Genet. 2006. PMID: 16323009
-
Players in Mitochondrial Dynamics and Female Reproduction.Front Mol Biosci. 2021 Oct 11;8:717328. doi: 10.3389/fmolb.2021.717328. eCollection 2021. Front Mol Biosci. 2021. PMID: 34708072 Free PMC article. Review.
-
OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy.Jpn J Ophthalmol. 2012 Jan;56(1):91-7. doi: 10.1007/s10384-011-0096-1. Epub 2011 Nov 1. Jpn J Ophthalmol. 2012. PMID: 22042570
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases