RESUMEN
Mutations in the PINK1 gene represent the second most frequent cause of early-onset Parkinson's disease (EOPD). One or two mutated alleles were also reported in some sporadic or familial patients suffering from late-onset Parkinson's disease (LOPD). We aimed at assessing the frequency of mutations in this gene in our population. We performed a sequence analysis of PINK1 in 115 patients diagnosed with Parkinson's disease (PD) from southern Italy, including 93 sporadic cases with EOPD, 9 familial cases with EOPD, and 13 familial cases with LOPD. Three known homozygous mutations (Q456X, W437X, Q126P), corresponding to a 2.6% of all cases, were found. In particular, one mutation was detected among the sporadic cases (1.0%), one mutation among the familial early-onset patients (11.1%) and one mutation among the familial late-onset patients (7.7%). In addition, we found two heterozygous mutations (E476K, R207Q) among the sporadic patients. Only one mutation (R207Q) had not been previously described. Our results assess the role played by PINK1 in EOPD in southern Italy and illustrate the existence of mutations in this gene also in the late-onset form of the disease.
Asunto(s)
Predisposición Genética a la Enfermedad , Mutación/genética , Trastornos Parkinsonianos/genética , Proteínas Quinasas/genética , Adulto , Edad de Inicio , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/epidemiología , Adulto JovenRESUMEN
Iron overload may lead to neurodegenerative disorders such as Parkinson's disease (PD) and alterations of iron-related genes might be involved in the pathogenesis of this disease. The gene of haemochromatosis (HFE) encodes the HFE protein which interacts with the transferrin receptor (TFR), lowering its affinity for iron-bound transferrin (TF). We examined four known polymorphisms, C282Y and H63D in the HFE gene, G258S in the TF gene and S82G in the TFR gene, in 181 sporadic PD patients and 180 controls from Southern Italy to investigate their possible role in susceptibility to PD. No significant differences were found in genotype and allele frequencies between PD and controls for all the polymorphisms studied, suggesting that these variants do not contribute significantly to the risk of PD.
Asunto(s)
Estudios de Asociación Genética/métodos , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Enfermedad de Parkinson/genética , Polimorfismo Genético/genética , Receptores de Transferrina/genética , Transferrina/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Proteína de la Hemocromatosis , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/metabolismo , Transferrina/metabolismoRESUMEN
The major component of Lewy Bodies (LB), the pathological hallmark of Parkinson's disease (PD) is α-synuclein, most prominently phosphorylated at serine 129. G-protein coupled receptor kinase 5 (GRK5) has been reported to phosphorylate α-synuclein in vitro, enhancing the α-synuclein toxicity to dopaminergic neurons in Drosophila model. Moreover, GRK5 was found in LBs from brain of PD patients. A genetic association study performed in the Japanese population revealed haplotypic association of the GRK5 gene with susceptibility to sporadic PD. We aimed at investigating whether four polymorphisms within the GRK5 gene (rs871196, rs2420616, rs7069375, rs4752293) could represent a risk factor for sporadic PD in Southern Italy. We genotyped 446 patients with PD and 450 controls for these markers and did not find any significant association with the disease at allelic, genotypic and haplotypic level. Our results indicate that the GRK5 gene does not confer risk to sporadic PD in our sample from Southern Italy.
Asunto(s)
Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Studies on heteroplasmy occurring in the mitochondrial DNA (mtDNA) control region (CR) in leukocytes of centenarians and younger subjects have shown that the C150T somatic transition is over-represented in centenarians. However, whether the occurrence/accumulation of heteroplasmy is a phenotypic consequence of extreme ageing or a genetically controlled event that may favor longevity is a question that deserves further attention. To clarify this point, we set up a Denaturing High Performance Liquid Chromatography (DHPLC) protocol to quantify mtDNA CR heteroplasmy. We then analyzed heteroplasmy in leukocytes of centenarians (100 subjects), their offspring and nieces/nephews (200 subjects, age-range 65-80 years, median age 70 years), and in leukocytes of 114 control subjects sex- and age-matched with the relatives of centenarians. RESULTS: The centenarians and their descendants, despite the different ages, showed similar levels of heteroplasmy which were significantly higher than levels in controls. In addition we found that heteroplasmy levels were significantly correlated in parent-offspring pairs (r = 0.263; p = 0.009), but were independent of mtDNA inherited variability (haplogroup and sequence analyses). CONCLUSION: Our findings suggest that the high degree of heteroplasmy observed in centenarians is genetically controlled, and that such genetic control is independent of mtDNA variability and likely due to the nuclear genome.
