Identification and characterization of the novel point mutation m.3634A>G in the mitochondrial MT-ND1 gene associated with LHON syndrome.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by bilateral acute or subacute progressive central visual loss. Most cases of LHON syndrome are caused by point mutations in the MT-ND1, MT-ND4, and MT-ND6 genes. Here, we report a novel homoplasmic mutation in the MT-ND1 gene (m.3634A>G, p.Ser110Gly) in a patient with the classical clinical features of LHON syndrome. Several observations support the idea that the mutation is pathogenic and involved in the clinical phenotype of the patient: 1) The mutation affected a highly conserved amino acid, 2) A pathogenic mutation in the same amino acid (m.3635G>A, p.Ser110Asn) was previously reported in a patient with LHON syndrome, 3) The mutation is not recorded in the Mitomap or Human Mitochondrial Genome Database, 4) In silico predictors classified the mutation as "probably damaging", and 5) Cybrids carrying the mutation showed decreased Complex I enzyme activity, lower cell proliferation, and decreased mitochondrial membrane potential relative to control cybrids.
Departament de Patología Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
Lidia
L
Carreño-Gago
Departament de neurología, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Josep
J
Gamez
Departament de Patología Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
Yolanda
Y
Cámara
Translational Bioinformatics, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Elena
E
Alvarez de la Campa
Departament de neurología, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Juan Sebastian
JS
Aller-Alvarez
Departament de neurofisiología, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Dulce
D
Moncho
Departament de neurología, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Maria
M
Salvado
Departament d'oftalmología, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Alicia
A
Galan
Translational Bioinformatics, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Spain.
Xavier
X
de la Cruz
Departament de Patología Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.
Tomàs
T
Pinós
Departament de Patología Mitocondrial i Neuromuscular, Hospital Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain; Àrea de Genètica Clínica i Molecular, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Electronic address: elena.garcia@vhir.org.
Elena
E
García-Arumí
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics; D050259:Genes, Mitochondrial; D006801:Humans; D008297:Male; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016415:Sequence Alignment
D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human
Cybrids; LHON syndrome; MT-ND1; Novel mutation; mtDNA