title: 3697G>A in MT-ND1 is a causative mutation in mitochondrial disease.
abstract: Mitochondrial diseases are a group of clinically heterogeneous disorders that can be difficult to diagnose. We report a two and a half year old girl with clinical symptoms compatible with Leigh disease but with no definitive diagnosis. Using next generation sequencing we found that mutation 3697G>A was responsible for the patient's clinical symptoms. Corroboration was performed via segregation analysis in mother and sister and by evolutionary analysis that showed that the mutation is located in a highly conserved region across a wide range of species. Functional analyses corroborated the mutation effect and indicated that the pathophysiological alterations were partially restored by Coenzyme Q10. In addition, we proposed that the presence of the mutation at high frequencies causes the phenotype in the patient, while other family members with intermediate levels of heteroplasmy are symptoms-free.
authors.affiliation: Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Lucía
authors.initials: L
authors.lastname: Spangenberg
authors.affiliation: Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Martín
authors.initials: M
authors.lastname: Graña
authors.affiliation: Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Greif
authors.affiliation: Centro Andaluz de Biología de Desarrollo (CABD), Universidad Pablo de Olavide/CSIC/Junta de Andalucía, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Suarez-Rivero
authors.affiliation: Laboratorio de Biotecnología Facultad de Ingeniería Universidad ORT Uruguay, Montevideo, Uruguay.
authors.forename: Karina
authors.initials: K
authors.lastname: Krysztal
authors.affiliation: Departamento de Genética, Facultad de Medicina, UDELAR, Montevideo, Uruguay.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Tapié
authors.affiliation: Departamento de Genética, Facultad de Medicina, UDELAR, Montevideo, Uruguay.
authors.forename: María
authors.initials: M
authors.lastname: Boidi
authors.affiliation: Servicio Médico Integral (SMI), Montevideo, Uruguay.
authors.forename: Valeria
authors.initials: V
authors.lastname: Fraga
authors.affiliation: Instituto de Genética Médica, Hospital Italiano, Montevideo, Uruguay.
authors.forename: Aída
authors.initials: A
authors.lastname: Lemes
authors.affiliation: Departamento de Genética, Facultad de Medicina, UDELAR, Montevideo, Uruguay.
authors.forename: Rosario
authors.initials: R
authors.lastname: Gueçaimburú
authors.affiliation: Centro de Rehabilitación Infantil Teletón, Montevideo, Uruguay.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cerisola
authors.affiliation: Centro Andaluz de Biología de Desarrollo (CABD), Universidad Pablo de Olavide/CSIC/Junta de Andalucía, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Sánchez-Alcázar
authors.affiliation: Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Carlos
authors.initials: C
authors.lastname: Robello
authors.affiliation: Departamento de Genética, Facultad de Medicina, UDELAR, Montevideo, Uruguay.
authors.forename: Victor
authors.initials: V
authors.lastname: Raggio
authors.affiliation: Institut Pasteur de Montevideo, Montevideo, Uruguay. Electronic address: naya@pasteur.edu.uy.
authors.forename: Hugo
authors.initials: H
authors.lastname: Naya
mesh_terms: D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D017354:Point Mutation; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; D014451:Ubiquinone; C024989:coenzyme Q10; C515075:NADH dehydrogenase subunit 1, human
keywords: Clinical genomics; Heteroplasmy; Leigh disease; Mitochondrial disease; Next Generation Sequencing