Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier

Tobias Bonifert, Kathrin N. Karle, Felix Tonagel, Marion Batra, Christian Wilhelm, Yvonne Theurer, Caroline Schoenfeld, Torsten Kluba, York Kamenisch, Valerio Carelli, Julia Wolf, Michael A. Gonzalez, Fiorella Speziani, Rebecca Schüle, Stephan L Zuchner, Ludger Schöls, Bernd Wissinger, Matthis Synofzik

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2164-2177
Number of pages14
JournalBrain
Volume137
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Optic Atrophy
Optic Nerve Diseases
Mutation
Phenotype
Mitochondrial Dynamics
Exome
Modifier
Optics
RNA Splice Sites
Gene Dosage
RNA Stability
Base Pairing
Exons
Nucleotides
Complementary DNA
Fibroblasts
Messenger RNA

Keywords

  • ataxia
  • cryptic exon
  • deep intronic mutation
  • genetic modifier
  • mitochondrial network

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Bonifert, T., Karle, K. N., Tonagel, F., Batra, M., Wilhelm, C., Theurer, Y., ... Synofzik, M. (2014). Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. Brain, 137(8), 2164-2177. https://doi.org/10.1093/brain/awu165

Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. / Bonifert, Tobias; 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; Zuchner, Stephan L; Schöls, Ludger; Wissinger, Bernd; Synofzik, Matthis.

In: Brain, Vol. 137, No. 8, 01.01.2014, p. 2164-2177.

Research output: Contribution to journalArticle

Bonifert, T, Karle, KN, Tonagel, F, Batra, M, Wilhelm, C, Theurer, Y, Schoenfeld, C, Kluba, T, Kamenisch, Y, Carelli, V, Wolf, J, Gonzalez, MA, Speziani, F, Schüle, R, Zuchner, SL, Schöls, L, Wissinger, B & Synofzik, M 2014, 'Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier', Brain, vol. 137, no. 8, pp. 2164-2177. https://doi.org/10.1093/brain/awu165
Bonifert T, Karle KN, Tonagel F, Batra M, Wilhelm C, Theurer Y et al. Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. Brain. 2014 Jan 1;137(8):2164-2177. https://doi.org/10.1093/brain/awu165
Bonifert, Tobias ; 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 ; Zuchner, Stephan L ; Schöls, Ludger ; Wissinger, Bernd ; Synofzik, Matthis. / Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier. In: Brain. 2014 ; Vol. 137, No. 8. pp. 2164-2177.
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abstract = "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.",
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N2 - 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.

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KW - ataxia

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