RESUMO
BACKGROUND: Mutations in the mitochondrial DNA (mtDNA) have been associated with aminoglycoside-induced and nonsyndromic deafness in different populations. In the present study, we investigated the contribution of mutations in mitochondrial genes to the etiology of hearing loss in a Brazilian sample. METHODS: Using mass spectrometry genotyping technology, combined with direct sequencing, 50 alterations previously described in 14 mitochondrial genes were screened in 152 patients with sensorineural hearing loss and in104 normal hearing controls. RESULTS: Fifteen known mitochondrial alterations were detected (G709A, A735G, A827G, G988A, A1555G, T4363C, T5628C, T5655C, G5821A, C7462T, G8363A, T10454C, G12236A, T1291C, G15927A). Pathogenic mutations in MT-RNR1 and MT-TK genes were detected in 3 % (5/152) of the patients with hearing loss. CONCLUSIONS: This study contributed to show the spectrum of mitochondrial variants in Brazilian patients with hearing loss. Frequency of A1555G was relatively high (2.6 %), indicating that this mutation is an important cause of hearing loss in our population. This work reports for the first time the investigation and the detection of the tRNA(Lys) G8363A mutation in Brazilian patients with maternally inherited sensorineural hearing loss.
Assuntos
DNA Mitocondrial/análise , Perda Auditiva Neurossensorial/genética , Mitocôndrias/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Brasil , Estudos de Casos e Controles , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Feminino , Genótipo , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , RNA de Transferência de Lisina/genéticaRESUMO
PURPOSE: There are many similarities in the clinical presentation of Leber hereditary optic neuropathy (LHON) and in patients who have optic neuropathy and a history of heavy tobacco and alcohol consumption. The main objective of this study is to investigate the frequency of primary and secondary mitochondrial DNA (mtDNA) mutations for LHON in patients diagnosed as having alcohol and tobacco optic neuropathy (ATON). METHODS: Twenty-six patients who had a history of heavy alcohol and tobacco consumption and who developed bilateral optic neuropathy were tested for primary mutations (G11778A, T14484C, and G3460A) by restriction analysis, and 14 secondary mutations in the genes mitochondrially encoded NADH dehydrogenase 1 (MT-ND1), mitochondrially encoded NADH dehydrogenase 4 (MT-ND4), mitochondrially encoded NADH dehydrogenase 4L (MT-ND4L), mitochondrially encoded NADH dehydrogenase 5 (MT-ND5), mitochondrially encoded NADH dehydrogenase 6 (MT-ND6), and mitochondrially encoded cytochrome B (MT-CYB) by direct sequencing. RESULTS: Four (15.4%) of 26 patients tested positive for LHON primary mutations, two for the G11778A mutation, and two for the T14484C mutation. No patient tested positive for any of the 14 secondary mutations. Familial recurrence was present in four patients, and only three of these patients have presented the LHON mutation. CONCLUSIONS: The diagnosis of LHON should be considered in all patients diagnosed as having optic neuropathy, particularly those with familial recurrence of vision loss.
Assuntos
Genes Mitocondriais , Isoenzimas/genética , Mitocôndrias/genética , Mutação , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas , Análise Mutacional de DNA , DNA Mitocondrial , Feminino , Humanos , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias/enzimologia , NADH Desidrogenase/metabolismo , Atrofia Óptica Hereditária de Leber/enzimologia , Reação em Cadeia da Polimerase , FumarRESUMO
PURPOSE: The aim of this study was to describe clinical features and search for primary mitochondrial DNA (mtDNA) mutations in 13 unrelated Brazilian patients with Leber's hereditary optic neuropathy (LHON). METHODS: Analysis of the G11778A, G3460A, and T14484C mutations was done by polymerase chain reaction and restriction fragment length polymorphism, and mutations were confirmed by direct sequencing. Mean age of onset was 24.5 years and all cases were bilateral. RESULTS: Sex ratio (12M:1F) and frequency of simultaneous involvement (9/13) were higher than in other studies. In nine cases there was familial recurrence: 24 male and two female relatives. Ten patients had a mutation: G11778A in six, T14484C in three and one G3460A. The frequency of patients bearing a primary mutation was lower than that described in multicentric studies but similar to that observed among Asians. A higher frequency of the T14484C mutation was detected. CONCLUSIONS: The contribution of Amerindians and Africans to the Brazilian mtDNA pool may account for differences in the type and frequency of primary LHON mutations.