Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy
Publication Date
February 14, 2018
Authors
Leonardo Caporali, Luisa Iommarini, Chiara La Morgia, Anna Olivieri, et al
Volume
14
Issue
2
Pages
e1007210
DOI
https://dx.plos.org/10.1371/journal.pgen.1007210
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1007210
Scopus
85043303250
Mendeley
http://www.mendeley.com/research/peculiar-combinations-individually-nonpathogenic-missense-mitochondrial-dna-variants-cause-low-penet
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Mendeley | Further Information

{"title"=>"Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy", "type"=>"journal", "authors"=>[{"first_name"=>"Leonardo", "last_name"=>"Caporali", "scopus_author_id"=>"35112686700"}, {"first_name"=>"Luisa", "last_name"=>"Iommarini", "scopus_author_id"=>"16549467300"}, {"first_name"=>"Chiara", "last_name"=>"La Morgia", "scopus_author_id"=>"7801365051"}, {"first_name"=>"Anna", "last_name"=>"Olivieri", "scopus_author_id"=>"8330210300"}, {"first_name"=>"Alessandro", "last_name"=>"Achilli", "scopus_author_id"=>"6701652869"}, {"first_name"=>"Alessandra", "last_name"=>"Maresca", "scopus_author_id"=>"36809311800"}, {"first_name"=>"Maria Lucia", "last_name"=>"Valentino", "scopus_author_id"=>"7004820682"}, {"first_name"=>"Mariantonietta", "last_name"=>"Capristo", "scopus_author_id"=>"36136558500"}, {"first_name"=>"Francesca", "last_name"=>"Tagliavini", "scopus_author_id"=>"37099067600"}, {"first_name"=>"Valentina", "last_name"=>"Del Dotto", "scopus_author_id"=>"56676223900"}, {"first_name"=>"Claudia", "last_name"=>"Zanna", "scopus_author_id"=>"6602169522"}, {"first_name"=>"Rocco", "last_name"=>"Liguori", "scopus_author_id"=>"25222055800"}, {"first_name"=>"Piero", "last_name"=>"Barboni", "scopus_author_id"=>"7004674365"}, {"first_name"=>"Michele", "last_name"=>"Carbonelli", "scopus_author_id"=>"14065681800"}, {"first_name"=>"Veronica", "last_name"=>"Cocetta", "scopus_author_id"=>"57079033900"}, {"first_name"=>"Monica", "last_name"=>"Montopoli", "scopus_author_id"=>"6506541648"}, {"first_name"=>"Andrea", "last_name"=>"Martinuzzi", "scopus_author_id"=>"7003610209"}, {"first_name"=>"Giovanna", "last_name"=>"Cenacchi", "scopus_author_id"=>"24793596400"}, {"first_name"=>"Giuseppe", "last_name"=>"De Michele", "scopus_author_id"=>"7005917994"}, {"first_name"=>"Francesco", "last_name"=>"Testa", "scopus_author_id"=>"7005677552"}, {"first_name"=>"Anna", "last_name"=>"Nesti", "scopus_author_id"=>"6603351971"}, {"first_name"=>"Francesca", "last_name"=>"Simonelli", "scopus_author_id"=>"7003553627"}, {"first_name"=>"Anna Maria", "last_name"=>"Porcelli", "scopus_author_id"=>"7003519117"}, {"first_name"=>"Antonio", "last_name"=>"Torroni", "scopus_author_id"=>"7005843426"}, {"first_name"=>"Valerio", "last_name"=>"Carelli", "scopus_author_id"=>"7005210889"}], "year"=>2018, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"621169310", "sgr"=>"85043303250", "scopus"=>"2-s2.0-85043303250", "doi"=>"10.1371/journal.pgen.1007210", "issn"=>"15537404"}, "id"=>"9821df32-addb-3adc-a7df-ed09ed813381", "abstract"=>"© 2018 Caporali et al. We here report on the existence of Leber’s hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband’s fibroblasts into the cybrid cell model. Finally, all but one of these missense mtDNA variants cluster along the same predicted fourth E-channel deputed to proton translocation within the transmembrane domain of Complex I, involving the ND1, ND4L and ND6 subunits. Hence, the definition of the pathogenic role of a specific mtDNA mutation becomes blurrier than ever and only an accurate evaluation of mitogenome sequence variation data from the general population, combined with functional analyses using the cybrid cell model, may lead to final validation. Our study conclusively shows that even in the absence of a clearly established LHON primary mutation, unprecedented combinations of missense mtDNA variants, individually known as polymorphisms, may lead to reduced OXPHOS efficiency sufficient to trigger LHON. In this context, we introduce a new diagnostic perspective that implies the complete sequence analysis of mitogenomes in LHON as mandatory gold standard diagnostic approach.", "link"=>"http://www.mendeley.com/research/peculiar-combinations-individually-nonpathogenic-missense-mitochondrial-dna-variants-cause-low-penet", "reader_count"=>3, "reader_count_by_academic_status"=>{"Researcher"=>1, "Professor"=>1, "Professor > Associate Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>1, "Professor"=>1, "Professor > Associate Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

Scopus | Further Information

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