title: The homozygous R504C mutation in MTO1 gene is responsible for ONCE syndrome.
abstract: We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: M Á
authors.initials: MÁ
authors.lastname: Martín
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Unidad de Enfermedades Metabólicas Hereditarias, Hospital 12 de Octubre, Madrid, Spain.|Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: García-Silva
authors.affiliation: Department of Genetics, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Barcia
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Delmiro
authors.affiliation: Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: Rodríguez-García
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Blázquez
authors.affiliation: Universidad Francisco de Vitoria, Facultad de Ciencias Experimentales, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Francisco-Álvarez
authors.affiliation: Unidad de Enfermedades Metabólicas Hereditarias, Hospital 12 de Octubre, Madrid, Spain.|Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Martín-Hernández
authors.affiliation: Unidad de Enfermedades Metabólicas Hereditarias, Hospital 12 de Octubre, Madrid, Spain.|Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Quijada-Fraile
authors.affiliation: Departamento de Oftalmología, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Tejada-Palacios
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Arenas
authors.affiliation: Universidad Francisco de Vitoria, Facultad de Ciencias Experimentales, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Santos
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Martínez-Azorín
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000140:Acidosis, Lactic; D000293:Adolescent; D000595:Amino Acid Sequence; D001927:Brain Diseases; D009202:Cardiomyopathies; D002352:Carrier Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases; D020125:Mutation, Missense; D009901:Optic Nerve Diseases; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C492006:MTO1 protein, human; D016601:RNA-Binding Proteins
keywords: MTO1; WES; encephalopathy; hypertrophic cardiomyopathy; mitochondria; mtDNA; optic atrophy