000150759 001__ 150759 000150759 005__ 20251017144650.0 000150759 0247_ $$2doi$$a10.1111/ceo.12355 000150759 0248_ $$2sideral$$a142795 000150759 037__ $$aART-2014-142795 000150759 041__ $$aeng 000150759 100__ $$aMartínez-Romero, Íñigo 000150759 245__ $$aNew MT-ND1 pathologic mutation for Leber hereditary optic neuropathy 000150759 260__ $$c2014 000150759 5060_ $$aAccess copy available to the general public$$fUnrestricted 000150759 5203_ $$aAbstractMutations causing Leber hereditary optic neuropathy are usually homoplasmic, show incomplete penetrance, and many of the affected positions are not well conserved through evolution. A large percentage of patients harbouring these mutations have no family history of disease. Moreover, the transfer of the mutation in the cybrid model is frequently not accompanied by the transfer of the cellular, biochemical and molecular phenotype. All these features make difficult their classification as the etiologic factors for this disease. We report a patient who exhibits typical clinical features of Leber hereditary optic neuropathy but lacks all three of the most common mitochondrial DNA mutations.MethodsThe diagnosis was made based on clinical studies. The mitochondrial DNA was completely sequenced, and the candidate mutation was analysed in more than 18 000 individuals around the world, its conservation index was estimated in more than 3100 species from protists to mammals, its position was modelled in the crystal structure of a bacteria ortholog subunit, and its functional consequences were studied in a cybrid model.ResultsGenetic analysis revealed an m.3472T>C transition in the MT‐ND1 gene that changes a phenylalanine to leucine at position 56. Bioinformatics, molecular‐genetic analysis and functional studies suggest that this transition is the etiological factor for the disorder.ConclusionsThis mutation expands the spectrum of deleterious changes in mitochondrial DNA‐encoded complex I polypeptides associated with this pathology and highlights the difficulties in assigning pathogenicity to new homoplasmic mutations that show incomplete penetrance in sporadic Leber hereditary optic neuropathy patients. 000150759 536__ $$9info:eu-repo/grantAgreement/ES/FIS/FI12/00217$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI10-00662$$9info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI11-01301 000150759 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es 000150759 590__ $$a2.347$$b2014 000150759 591__ $$aOPHTHALMOLOGY$$b18 / 57 = 0.316$$c2014$$dQ2$$eT1 000150759 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion 000150759 700__ $$aHerrero-Martín, M Dolores 000150759 700__ $$0(orcid)0000-0002-4379-1100$$aLlobet, Laura$$uUniversidad de Zaragoza 000150759 700__ $$0(orcid)0000-0001-5964-6138$$aEmperador, Sonia 000150759 700__ $$aMartín-Navarro, Antonio 000150759 700__ $$aNarberhaus, Bernat 000150759 700__ $$0(orcid)0000-0001-9876-5850$$aAscaso, Francisco J$$uUniversidad de Zaragoza 000150759 700__ $$0(orcid)0000-0002-3217-1424$$aLópez-Gallardo, Ester$$uUniversidad de Zaragoza 000150759 700__ $$0(orcid)0000-0003-1770-6299$$aMontoya, Julio$$uUniversidad de Zaragoza 000150759 700__ $$0(orcid)0000-0002-0269-7337$$aRuiz-Pesini, Eduardo$$uUniversidad de Zaragoza 000150759 7102_ $$11004$$2646$$aUniversidad de Zaragoza$$bDpto. Cirugía,Ginecol.Obstetr.$$cÁrea Oftalmología 000150759 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000150759 773__ $$g42, 9 (2014), 856-864$$pCLIN EXP OPHTHALMOL$$tCLINICAL AND EXPERIMENTAL OPHTHALMOLOGY$$x1442-6404 000150759 8564_ $$s557333$$uhttps://zaguan.unizar.es/record/150759/files/texto_completo.pdf$$yPostprint 000150759 8564_ $$s2918295$$uhttps://zaguan.unizar.es/record/150759/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint 000150759 909CO $$ooai:zaguan.unizar.es:150759$$particulos$$pdriver 000150759 951__ $$a2025-10-17-14:36:02 000150759 980__ $$aARTICLE