Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier
| Autor: | Marion Batra, Tobias Bonifert, Valerio Carelli, Michael A. Gonzalez, Yvonne Theurer, Caroline Schoenfeld, Ludger Schöls, Bernd Wissinger, Fiorella Speziani, Rebecca Schüle, Torsten Kluba, Kathrin N. Karle, Felix Tonagel, Stephan Züchner, Christian Wilhelm, Matthis Synofzik, Julia Wolf, York Kamenisch |
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| Přispěvatelé: | Bonifert, Tobia, Karle, Kathrin N., Tonagel, Felix, Batra, Marion, Wilhelm, Christian, Theurer, Yvonne, Schoenfeld, Caroline, Kluba, Torsten, Kamenisch, York, Carelli, Valerio, Wolf, Julia, Gonzalez, Michael A., Speziani, Fiorella, Schüle, Rebecca, Züchner, Stephan, Schöls, Ludger, Wissinger, Bernd, Synofzik, Matthis |
| Rok vydání: | 2014 |
| Předmět: |
Male
Gene Dosage OPA1 protein human medicine.disease_cause Compound heterozygosity GTP Phosphohydrolases GTP Phosphohydrolase Optic neuropathy pathology [Optic Atrophy Autosomal Dominant] Exon Missense mutation Exome sequencing mitochondrial network Genetics genetic modifier Mutation food and beverages genetics [Exons] Exons Syndrome Middle Aged cryptic exon Pedigree Phenotype Female classification [Optic Atrophy Autosomal Dominant] Human Adult genetics [GTP Phosphohydrolases] endocrine system Adolescent genetics [Optic Atrophy Autosomal Dominant] Single-nucleotide polymorphism genetics [Mutation] genetics [Genetic Loci] Biology Atrophy Arts and Humanities (miscellaneous) deep intronic mutation Optic Atrophy Autosomal Dominant medicine Humans ddc:610 genetics [Genome Human] Aged Genome Human ataxia fungi Genetic Variation genetics [Gene Dosage] Original Articles medicine.disease Molecular biology eye diseases Genetic Loci Neurology (clinical) |
| Zdroj: | Brain 137(8), 2164-2177 (2014). doi:10.1093/brain/awu165 |
| ISSN: | 1460-2156 |
| DOI: | 10.1093/brain/awu165 |
| Popis: | The genetic basis of many optic neuropathies remains unclear. Bonifert et al. show that deep intronic OPA1 mutations can account for the disease in a number of previously unsolved cases. Moreover, an OPA1 modifier variant can generate syndromic 'optic atrophy plus' phenotypes if combined in trans with a loss-of-function OPA1 mutation.The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic 'optic atrophy plus' phenotypes in several families. First, we unravelled a deep intronic mutation 364 base pairs 3' of exon 4b in OPA1 by in-depth investigation of a family with severe optic atrophy plus syndrome in which conventional OPA1 diagnostics including gene dosage analyses were normal. The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis. In patient fibroblasts we demonstrate nonsense mediated messenger RNA decay, reduced levels of OPA1 protein, and impairment of mitochondrial dynamics. Subsequent site-specific screening of > 360 subjects with unexplained inherited optic neuropathy revealed three additional families carrying this deep intronic mutation and a base exchange four nucleotides upstream, respectively, thus confirming the clinical significance of this mutational mechanism. Second, in all severely affected patients of the index family, the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2). The variant alone did not cause a phenotype, even in homozygous state indicating that this long debated OPA1 variant is not pathogenic per se, but acts as a phenotypic modifier if it encounters in trans with an OPA1 mutation. Subsequent screening of whole exomes from > 600 index patients identified a second family with severe optic atrophy plus syndrome due to compound heterozygous p.I382M, thus confirming this mechanism. In summary, we provide genetic and functional evidence that deep intronic mutations in OPA1 can cause optic atrophy and explain disease in a substantial share of families with unsolved inherited optic neuropathies. Moreover, we show that an OPA1 modifier variant explains the emergence of optic atrophy plus phenotypes if combined in trans with another OPA1 mutation. Both mutational mechanisms identified in this study-deep intronic mutations and intragenic modifiers-might represent more generalizable mechanisms that could be found also in a wide range of other neurodegenerative and optic neuropathy diseases |
| Databáze: | OpenAIRE |
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