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1.
JIMD Rep ; 22: 39-45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25732997

RESUMO

In a 28-year-old male with a mild mitochondrial myopathy manifesting as exercise intolerance and early signs of cardiomyopathy without muscle weakness or ophthalmoplegia, we identified two novel mutations in the SLC25A4 gene: c.707G>C in exon 3 (p.(R236P)) and c.116_137del in exon 2 (p.(Q39Lfs*14)). Serum lactate levels at rest were elevated (12.7 mM). Both the patient's father and brother were heterozygous carriers of the c.707G>C mutation and were asymptomatic. The second mutation causes a 22 bp deletion leading to a frame shift likely giving rise to a premature stop codon and nonsense-mediated decay (NMD). The segregation of the mutations could not be tested directly as the mother had died before. However, indirect evidence from NMD experiments showed that the two mutations were situated on two different alleles in the patient. This case is unique compared to other previously reported patients with either progressive external ophthalmoplegia (PEO) or clear hypertrophic cardiomyopathy with exercise intolerance and/or muscle weakness carrying recessive mutations leading to a complete absence of the SLC25A4 protein. Most likely in our patient, although severely reduced, SLC25A4 is still partially present and functional.

2.
J Med Genet ; 49(1): 10-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22114105

RESUMO

BACKGROUND: Mitochondrial disorders are associated with abnormalities of the oxidative phosphorylation (OXPHOS) system and cause significant morbidity and mortality in the population. The extensive clinical and genetic heterogeneity of these disorders due to a broad variety of mutations in several hundreds of candidate genes, encoded by either the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), impedes a straightforward genetic diagnosis. A new disease gene is presented here, identified in a single Kurdish patient born from consanguineous parents with neonatally fatal Leigh syndrome and complex I deficiency. METHODS AND RESULTS: Using homozygosity mapping and subsequent positional candidate gene analysis, a total region of 255.8 Mb containing 136 possible mitochondrial genes was identified. A pathogenic mutation was found in the complex I subunit encoding the NDUFA9 gene, changing a highly conserved arginine at position 321 to proline. This is the first disease-causing mutation ever reported for NDUFA9. Complex I activity was restored in fibroblasts of the patient by lentiviral transduction with wild type but not mutant NDUFA9, confirming that the mutation causes the complex I deficiency and related disease. CONCLUSIONS: The data show that homozygosity mapping and candidate gene analysis remain an efficient way to detect mutations even in small consanguineous pedigrees with OXPHOS deficiency, especially when the enzyme deficiency in fibroblasts allows appropriate candidate gene selection and functional complementation.


Assuntos
Complexo I de Transporte de Elétrons/genética , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Células Cultivadas , Consanguinidade , Análise Mutacional de DNA , Complexo I de Transporte de Elétrons/metabolismo , Evolução Fatal , Estudos de Associação Genética , Homozigoto , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Neuroimagem
3.
Mitochondrion ; 11(6): 964-72, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21946566

RESUMO

The mitochondrial DNA (mtDNA) is highly variable, containing large numbers of pathogenic mutations and neutral polymorphisms. The spectrum of homoplasmic mtDNA variation was characterized in 730 subjects and compared with known pathogenic sites. The frequency and distribution of variants in protein coding genes were inversely correlated with conservation at the amino acid level. Analysis of tRNA secondary structures indicated a preference of variants for the loops and some acceptor stem positions. This comprehensive overview of mtDNA variants distinguishes between regions and positions which are likely not critical, mainly conserved regions with pathogenic mutations and essential regions containing no mutations at all.


Assuntos
Sequência Conservada , DNA Mitocondrial/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , DNA Mitocondrial/química , Humanos , Lactente , Pessoa de Meia-Idade , Conformação de Ácido Nucleico , Polimorfismo Genético , RNA de Transferência/genética , Análise de Sequência de DNA , Adulto Jovem
5.
J Med Genet ; 47(8): 507-12, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19542079

RESUMO

BACKGROUND: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene. METHODS AND RESULTS: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers. CONCLUSIONS: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations.


Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Doença de Leigh/enzimologia , Doença de Leigh/genética , Metiltransferases/genética , Proteínas Mitocondriais/genética , Mutação/genética , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Complexo I de Transporte de Elétrons/genética , Família , Feminino , Homozigoto , Humanos , Doença de Leigh/diagnóstico por imagem , Doença de Leigh/metabolismo , Leucócitos Mononucleares/enzimologia , Imageamento por Ressonância Magnética , Masculino , Metiltransferases/química , Proteínas Mitocondriais/química , Dados de Sequência Molecular , Marrocos , Linhagem , Tomografia Computadorizada por Raios X , Adulto Jovem
6.
Genomics ; 91(1): 52-60, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18060737

RESUMO

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by left ventricular hypertrophy (LVH) predominantly affecting the interventricular septum. Cardiac myosin-binding protein C (cMyBP-C) mutations are common causes of FHC. Gene expression profiling was performed in left ventricles of 9-week-old wild-type mice, heterozygous cMyBP-C KO mice displaying asymmetric septal hypertrophy, and homozygous mice developing eccentric LVH. Knocking out one or two cMyBP-C genes leads primarily to gene expression changes indicating an increased energy demand, activation of the JNK and p38 parts of the MAPK pathway and deactivation of the ERK part, and induction of apoptosis. Altered gene expression for processes related to cardiac structure, contractile proteins, and protein turnover was also identified. Many of the changes were more pronounced in the homozygous KO mice. These alterations point to physiological and pathological adaptations in the prehypertrophic heterozygous KO mice and the hypertrophic homozygous mice.


Assuntos
Cardiomiopatia Hipertrófica Familiar/metabolismo , Proteínas de Transporte/metabolismo , Transtornos Cromossômicos/metabolismo , Regulação da Expressão Gênica , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Animais , Apoptose/genética , Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/patologia , Proteínas de Transporte/genética , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , MAP Quinases Reguladas por Sinal Extracelular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Heterozigoto , Homozigoto , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Miocárdio/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Septo Interventricular/metabolismo , Septo Interventricular/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Genomics ; 88(4): 480-8, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16781840

RESUMO

Cardiac hypertrophy is an important risk factor for cardiac morbidity and mortality. To unravel the underlying pathogenic genetic pathways, we hybridized left ventricular RNA from Transverse Aortic Constriction mice at 48 h, 1 week, and 2, 3, and 8 weeks after surgery to microarrays containing a 15K fetal cDNA collection. Key processes involved an early restriction in the expression of metabolic genes, accompanied by increased expression of genes related to growth and reactivation of fetal genes. Most of these genes returned to basal expression levels during the later, compensated hypertrophic phase. Our findings suggest that compensated hypertrophy in these mice is established by rapid adaptation of the heart at the cost of gene expression associated with metabolic activity, with only temporary expression of possible maladaptive processes. Therefore, the transient early changes may reflect a beneficial response to pressure overload, as deterioration of cardiac hemodynamic function or heart failure does not occur.


Assuntos
Cardiomegalia/genética , Regulação da Expressão Gênica , Animais , Aorta/cirurgia , Cardiomegalia/etiologia , Modelos Animais de Doenças , Metabolismo Energético/genética , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/genética , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Pressão Ventricular
8.
Neuromuscul Disord ; 14(10): 683-8, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15351426

RESUMO

Screening the mitochondrial DNA of a 64-year-old woman with mitochondrial myopathy revealed 76% of the tRNA(Leu(UUR)) A3302G mutation in muscle. Muscle of her affected son carried 96% mutated mitochondrial DNA. Both patients were biopsied twice, showing isolated complex I deficiency in the son's first biopsy, additional increased (within normal range) complex II + III activities in his second biopsy, combined complex I, II + III deficiency in mothers first biopsy and additional complex IV deficiency in her second biopsy. After a stay in the mountains, the son died of cardiac arrhythmia. The A3302G mutation has been reported before and is associated with mitochondrial myopathy and cardiorespiratory failure. Pathogenesis is explained by abnormal mtRNA processing, which was also reported for the adjacent C3303T mutation associated with cardiomyopathy and/or skeletal myopathy. Our findings suggest that a high mutation load of the A3302G mutation can lead to fatal cardiorespiratory failure, likely triggered by low environmental oxygen pressure and exercise.


Assuntos
DNA Mitocondrial/genética , Parada Cardíaca/genética , Miopatias Mitocondriais/genética , Mutação , RNA de Transferência de Leucina/genética , Risco , Adulto , Análise Mutacional de DNA/métodos , Feminino , Parada Cardíaca/etiologia , Parada Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia
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