RESUMO
OBJECTIVE: To define the molecular basis of the autosomal dominant progressive external ophthalmoplegia and parkinsonism in a large family with a dominantly transmitted multiple mitochondrial DNA deletion disorder. DESIGN: Microsatellite analysis and screening of the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1), and polymerase gamma-1 (POLG1) genes. RESULTS: We identified 3 novel heterozygous POLG1 substitutions in the same family. Autosomal dominant progressive external ophthalmoplegia segregated with 1532G>A in exon 8 and an intronic variant c.2070 + 158G>A in cis. The one patient with parkinsonism had an additional heterozygous substitution in exon 7 in trans (1389G>T). Both coding region mutations were predicted to alter conserved amino acids in the linker region of polymerase gamma. None of the substitutions were found in 192 ethnically matched control chromosomes, 108 patients with progressive external ophthalmoplegia, nor 140 cases of sporadic idiopathic Parkinson disease. CONCLUSION: Both autosomal dominant progressive external ophthalmoplegia and parkinsonism can because caused by mutations that directly affect the polymerase domain of polymerase gamma.
Assuntos
Anormalidades Múltiplas/genética , DNA Polimerase Dirigida por DNA/genética , Mutação , Oftalmoplegia Externa Progressiva Crônica/patologia , Transtornos Parkinsonianos/patologia , Anormalidades Múltiplas/patologia , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , DNA Polimerase gama , Saúde da Família , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido NucleicoRESUMO
BACKGROUND: Human genome evolution has been shaped by infectious disease. Although most genetic studies have focused on the immune system, recovery after sepsis is directly related to physiological reserve that is critically dependent on mitochondrial function. We investigated whether haplogroup H, the most common type of mitochondrial DNA (mtDNA) in Europe, contributes to the subtle genetic variation in survival after sepsis. METHODS: In a prospective study, we included 150 individuals who were sequentially admitted to the intensive care unit in a hospital in Newcastle upon Tyne, UK. After clinical data were obtained, patients underwent mtDNA haplotyping by analysis with PCR and restriction fragment length polymorphism. As endpoints, we used death during the 6-month period or survival at 6 months. FINDINGS: Follow-up was complete for all study participants, although the haplotype of two patients could not be reliably determined. On admission to the intensive care unit, the frequency of mtDNA haplogroup H in study patients did not differ between study patients admitted with severe sepsis and 542 age-matched controls from the northeast of England. MtDNA haplogroup H was a strong independent predictor of outcome during severe sepsis, conferring a 2.12-fold (95% CI 1.02-4.43) increased chance of survival at 180 days compared with individuals without the haplogroup H. INTERPRETATION: Although haplogroup H is the most recent addition to the group of European mtDNA, paradoxically it is also the most common. Increased survival after sepsis provides one explanation for this observation. MtDNA haplotyping offers a new means of risk stratification of patients with severe infections, which suggests new avenues for therapeutic intervention.
Assuntos
DNA Mitocondrial/genética , Haplótipos/genética , Sepse/mortalidade , APACHE , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/classificação , Sepse/imunologiaRESUMO
A genetic susceptibility to depression in PD, acting via the serotonergic system, has been suggested. We examined the influence of allelic variation (L/S) in a functional polymorphism in the serotonin transporter (5-HTTLPR) gene upon mood in 108 PD patients and 82 controls. Using a logistic regression model we found no evidence for an association between 5-HTTLPR genotypes, or the presence of the S allele, and depression.
Assuntos
Depressão/genética , Doença de Parkinson/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Idoso , Alelos , Depressão/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Variação Genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Regiões Promotoras Genéticas/genética , Fatores de RiscoRESUMO
There is increasing evidence that genetic variants of mitochondrial DNA have an important role in the cause of idiopathic Parkinson's disease. We determined the mitochondrial DNA haplogroup of 455 Parkinson's disease cases, 185 Alzheimer's disease cases, and 447 healthy English control subjects. The UKJT haplogroup cluster was associated with a 22% reduction in population-attributable risk for Parkinson's disease. There was no association between individual haplogroups or the UKJT cluster and Alzheimer's disease, confirming that the association with Parkinson's disease was disease specific and not a general effect seen in all neurodegenerative diseases.