Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

Baris, Olivier; Delettre, Cécile; Amati‐Bonneau, Patrizia; Surget, Marie-Odile; Charlin, J.-F.; Catier, A.; Derieux, Laurence; Guyomard, Jean Laurent; Dollfus, Hélène; Jonveaux, Philippe; Ayuso, Carmen; Maumenee, Irene H.; Lorenz, Birgit; Mohammed, Shehla; Tourmen, Yves; Bonneau, Dominique; Malthièry, Yves; Hamel, Christian; Reynier, Pascal

doi:10.1002/humu.9152

Cited by 53 publications

(44 citation statements)

References 16 publications

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“…One of the ESSs that we have in our results and that is validated experimentally is TAGTTAG, a 7-mer ESS, which binds to the splicing repressor hnRNP A1 (Millevoi et al, 2010). Another 7-mer exon silencer is TTAAGGT (Baris et al, 2003), which is involved in optic atrophy disease.…”

Section: Badr and Heathsupporting

confidence: 66%

Identifying Splicing Regulatory Elements with de Bruijn Graphs

Badr

Heath²

2014

Journal of Computational Biology

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Splicing regulatory elements (SREs) are short, degenerate sequences on pre-mRNA molecules that enhance or inhibit the splicing process via the binding of splicing factors, proteins that regulate the functioning of the spliceosome. Existing methods for identifying SREs in a genome are either experimental or computational. Here, we propose a formalism based on de Bruijn graphs that combines genomic structure, word count enrichment analysis, and experimental evidence to identify SREs found in exons. In our approach, SREs are not restricted to a fixed length (i.e., k-mers, for a fixed k). As a result, we identify 2001 putative exonic enhancers and 3080 putative exonic silencers for human genes, with lengths varying from 6 to 15 nucleotides. Many of the predicted SREs overlap with experimentally verified binding sites. Our model provides a novel method to predict variable length putative regulatory elements computationally for further experimental investigation.

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Section: Badr and Heathsupporting

confidence: 66%

Identifying Splicing Regulatory Elements with de Bruijn Graphs

Badr

Heath²

2014

Journal of Computational Biology

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“…The sequencing of OPA1 has now brought to light a much wider clinical spectrum including severe forms of neonatal onset (Baris et al, 2003), acute onset identical to LHON (Bonneau, et al, manuscript in preparation), late onset (Johnston et al, 1999), association of optic atrophy with extra-ocular symptoms (Amati-Bonneau et al, 2007), and optic atrophy with spontaneous visual recovery (Cornille et al, 2008). However, the phenotypical expression of OPA1 mutations is highly variable, even within a given family, and genotype-phenotype correlations are very scarce.…”

Section: Discussionmentioning

confidence: 99%

Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novelOPA1mutations

et al. 2009

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ABSTRACT:We report the results of molecular screening in 980 patients carried out as part of their work-up for suspected hereditary optic neuropathies. All the patients were investigated for Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), by searching for the ten primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes, the two genes currently identified in ADOA. Molecular defects were identified in 440 patients (45% of screened patients). Among these, 295 patients (67%) had OFFICIAL JOURNAL www.hgvs.org E693 Molecular Screening of 980 Cases of Suspected Hereditary Optic Neuropathyan OPA1 mutation, 131 patients (30%) had an mtDNA mutation, and 14 patients (3%), belonging to three unrelated families, had an OPA3 mutation. Interestingly, OPA1 mutations were found in 157 (40%) of the 392 apparently sporadic cases of optic atrophy. The eOPA1 locus-specific database now contains a total of 204 OPA1 mutations, including 77 novel OPA1 mutations reported here. The statistical analysis of this large set of mutations has led us to propose a diagnostic strategy that should help with the molecular work-up of optic neuropathies. Our results highlight the importance of investigating LHON-causing mtDNA mutations as well as OPA1 and OPA3 mutations in cases of suspected hereditary optic neuropathy, even in absence of a family history of the disease.

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“…De novo OPA1 mutations have been reported in the literature before. In one report, OPA1 testing in 20 patients with ADOA and no family history revealed two cases (10%) with de novo OPA1 mutations (Baris et al, 2003). In a larger study, mutation screening for LHON, OPA1 and OPA3 genes was performed in 980 patients with suspected hereditary optic neuropathy (Ferré et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identified a novelde novo OPA1mutation in a consanguineous family presenting with optic atrophy

et al. 2016

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SummaryInherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.

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Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

Cited by 53 publications

References 16 publications

Identifying Splicing Regulatory Elements with de Bruijn Graphs

Identifying Splicing Regulatory Elements with de Bruijn Graphs

Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novelOPA1mutations

Exome sequencing identified a novelde novo OPA1mutation in a consanguineous family presenting with optic atrophy

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