ABSTRACT
Some studies have suggested an overlap of clinical and genetic findings between essential tremor (ET) and Parkinson's disease (PD). The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene. Since patients with PD have higher LINGO1 expression levels compared to healthy controls, and animal models of PD show elevated LINGO1 protein levels after experimentally induced damage in the striatum, it can be inferred that LINGO1 is probably involved in PD pathophysiology. In this study, we performed a genetic association analysis of the rs9652490 and rs11856808 SNPs in Italian PD patients and controls to assess the role of these variants in our population. A total of 567 patients with PD and 468 control subjects were enrolled in five Movement Disorder centers located in Central-Southern Italy. Both variants were significantly associated with PD under a recessive model of inheritance before applying the Bonferroni correction. The GG genotype of rs9652490 and the TT genotype of rs11856808 were less frequent in patients than in controls, suggesting a protective effect against the disease. However, after stringent correction, only the P-values obtained from allele and genotype comparisons of the rs11856808 SNP remained significant. Our findings suggest that LINGO1 plays a certain role in the development of PD in the Italian population and represents an interesting candidate gene responsible for PD, due to its involvement in neurological processes.
Subject(s)
Genome-Wide Association Study/methods , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Aged , Cohort Studies , Female , Humans , Italy/epidemiology , Italy/ethnology , Male , Middle Aged , Parkinson Disease/epidemiology , Parkinson Disease/ethnology , Polymorphism, Single Nucleotide/geneticsABSTRACT
The range of the genus Talpa covers almost all Europe up to Western Asia. This genus has never been the object of comprehensive systematic studies using molecular and genetic techniques, such that the evolutionary relationships among species remain unclear. Talpa shows high levels of endemism, and the influence of past glaciation cycles on the distribution pattern of several species has been hypothesized. In this work, we assessed the molecular systematics of the genus using the mitochondrial gene cytochrome b from eight of the nine extant species of Talpa moles. Furthermore, molecular clock estimations were used to hypothesize a biogeographic scenario in concordance with fossil data. Results suggest a monophyletic origin of the genus and a common ancestor for the western European moles T. europaea, T. caeca, T. romana and T. occidentalis. The eastern species T. altaica and T. caucasica are basally divergent. The estimated ages of divergence among lineages are in accordance with a Miocene origin of the extant moles. The genus likely originated in Asia, spreading into Europe during the Pliocene. The evolution of moles appears to have been driven by changes in moisture levels that influenced extinction and speciation events during the Miocene and the Pliocene. Pleistocene climatic oscillations likely caused the range shrinkages and expansions that led to the current distribution pattern of most Talpa species.
Subject(s)
Evolution, Molecular , Moles/genetics , Phylogeny , Animals , Bayes Theorem , Cytochromes b/genetics , DNA, Mitochondrial/genetics , Geography , Likelihood Functions , Models, Genetic , Moles/classification , Sequence Analysis, DNAABSTRACT
Mutations in the gene DJ-1 have been shown to be a rare cause of early-onset Parkinson's disease (EOPD). Since DJ-1 mutations have been found in patients with Parkinson's disease (PD) from southern Italy, we aimed to investigate whether polymorphisms within the DJ-1 gene could represent a risk factor for sporadic PD. First, we genotyped 294 patients with PD and 298 controls coming from southern Italy to assess the distribution of the insertion/deletion (Ins/Del) polymorphism. In a second phase, we identified five single-nucleotide polymorphisms (SNPs) useful to delimit a region potentially involved and genotyped all patients and controls for these markers. All the markers analyzed were significantly associated with PD at both allelic and genotypic level. The most significant association with the disease was found at the Ins/Del polymorphism (p = 0.0001; adjusted odds ratio (OR ) = 2.05; confidence interval (CI ) = 1.36-3.08). When we considered a three-marker sliding window, we found a highly significant association between the disease and the haplotypes including markers rs17523802, Ins/Del, and rs3766606 (p = 0.0007) and markers Ins/Del, rs3766606 and rs7517357 (p = 0.0054). Our results indicate that polymorphisms located in a region spanning 3535 bp from the promoter to the intron 2 of the DJ-1 gene confer risk to sporadic PD in southern Italy.
Subject(s)
Genetic Predisposition to Disease , Intracellular Signaling Peptides and Proteins/genetics , Oncogene Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Genetic , Adult , Aged , Aged, 80 and over , Female , Genetic Markers , Genotype , Humans , Italy , Male , Middle Aged , Protein Deglycase DJ-1 , Risk FactorsSubject(s)
Epilepsies, Myoclonic/genetics , Mutation , Nerve Tissue Proteins/genetics , Nucleotides/genetics , Sodium Channels/genetics , Base Sequence , Case-Control Studies , Codon , DNA Mutational Analysis , Gene Deletion , Humans , Infant, Newborn , Introns , Italy , Molecular Sequence Data , NAV1.1 Voltage-Gated Sodium ChannelABSTRACT
Dementia is a common complication of Parkinson's disease (PD). It correlates significantly with the presence of cortical, limbic or nigral Lewy bodies, mainly constituted of alpha-synuclein. Mutations of the alpha-synuclein gene (SNCA) have been linked to rare familial forms of PD, while association studies on the promoter polymorphisms have given conflicting results in sporadic patients. We have performed a case control study to investigate whether genetic variability in the promoter of the alpha-synuclein gene could predispose to dementia in PD. A total of 114 demented patients and 114 non-demented patients with sporadic PD were included in the study. Six polymorphic loci (including the Rep1 microsatellite) in the promoter of the SNCA gene were examined. Each marker, taken individually, did not show association to dementia and no significant differences were observed in the inferred haplotype frequencies of demented and non-demented patients. Our data suggest the lack of involvement of the SNCA promoter in the pathogenesis of dementia in PD. Further studies in other populations are needed to confirm these results.
Subject(s)
Dementia/genetics , Haplotypes , Parkinson Disease/genetics , Promoter Regions, Genetic , alpha-Synuclein/genetics , Aged , Female , Humans , Male , Middle Aged , Polymorphism, GeneticSubject(s)
Gene Dosage , Nerve Tissue Proteins/genetics , Spinocerebellar Ataxias/genetics , Adult , Age of Onset , Aged , Alleles , Ataxins , Family Health , Female , Genes, Dominant , Humans , Male , Middle Aged , Nucleotides/genetics , PedigreeSubject(s)
Parkinson Disease/genetics , Point Mutation , Protein Serine-Threonine Kinases/genetics , Adult , Age of Onset , Aged , Aged, 80 and over , Case-Control Studies , Female , Genes, Dominant , Haplotypes , Heterozygote , Humans , Italy , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Male , Middle AgedSubject(s)
Chylomicrons/metabolism , Guanine Nucleotide Exchange Factors/genetics , Hypobetalipoproteinemia, Familial, Apolipoprotein B/genetics , Monomeric GTP-Binding Proteins/genetics , Mutation , Spinocerebellar Degenerations/genetics , Base Sequence , Homozygote , Humans , Male , Molecular Sequence Data , Pedigree , Sequence Analysis, DNA , Vitamin E/bloodSubject(s)
Hypotension/genetics , Nerve Tissue Proteins/genetics , RNA-Binding Proteins/genetics , Tremor/genetics , Trinucleotide Repeats , Aged , Alleles , Blood Pressure Monitoring, Ambulatory , Fragile X Mental Retardation Protein , Heterozygote , Humans , Male , Postprandial Period , Promoter Regions, Genetic/geneticsABSTRACT
We investigated the segregation of the dinucleotide GT repeat polymorphism in the intron between exons 9 and 10 of the tau gene in 300 patients with Parkinson's disease (PD) and in 197 normal controls. The A3 allele was more frequent in cases than in controls (30% versus 16%, p<0.001), and individuals carrying at least one A3 allele in their genotype had an increased risk of developing PD (odds ratio 2.78, 95% confidence interval 1.81-4.29). No significant differences were found between patients by considering the age at onset and the presence of family history or dementia. Our findings suggest a possible involvement of the tau gene in the pathogenesis of PD.
Subject(s)
Parkinson Disease/genetics , Polymorphism, Genetic , tau Proteins/genetics , Age of Onset , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Dinucleotide Repeats , Exons , Female , Gene Frequency , Genetic Predisposition to Disease , Genomics , Humans , Introns , Male , Mental Status Schedule , Middle Aged , Parkinson Disease/bloodABSTRACT
Contradictory evidence has been reported on the role of the polymorphic mixed dinucleotide repeat (NACP-REP1) of the alpha-synuclein gene as a risk factor for sporadic Parkinson's disease (PD). In the present study we genotyped the NACP-REP1 polymorphism in 189 PD patients from southern Italy and 182 healthy control subjects. We failed to demonstrate an association of any NACP-REP1 allele with PD.
Subject(s)
Dinucleotide Repeats/genetics , Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Genetic/genetics , Aged , Aged, 80 and over , Case-Control Studies , Female , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Genetic Testing , Genotype , Humans , Italy/epidemiology , Male , Middle Aged , Nerve Tissue Proteins/biosynthesis , Parkinson Disease/epidemiology , Synucleins , alpha-SynucleinSubject(s)
Chromosome Mapping , DNA, Ribosomal/genetics , Perciformes/genetics , RNA, Ribosomal, 5S/genetics , RNA, Ribosomal/genetics , Repetitive Sequences, Nucleic Acid , Animals , Base Sequence , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Nucleolus Organizer Region/genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Sequence Homology, Nucleic AcidABSTRACT
The contact zone between the Ancarano (ACR; 2n = 24) and Cittaducale (CD; 2n = 22) races of Mus musculus domesticus was studied. We used chromosomes and mitochondrial DNA (mtDNA) sequences of the control region as genetic markers to detect introgression between races. In total, 76 mice were trapped at 17 localities. Cytogenetic analysis was performed on 73 mice. A segment of the control region (468 bp) was sequenced in 41 specimens. The two races are distributed parapatrically and the contact zone was identified inside a village (Pizzoli). No mixed population was found in the study area. The contact zone does not correspond to any geographical or ecological barrier but is located in a zone of potentially high density of mice. The sequence analysis clearly demonstrates genetic differentiation between races (1.4% of sequence divergence). Hybridization is rare. Evidence of introgression was found in two individuals in the contact zone: one individual of the ACR race carries a metacentric belonging to the CD race, while another ACR individual carries a CD-like haplotype. In these ecological conditions, the observed distribution pattern and the very low level of hybridization suggest the presence of a premating mechanism of reproductive isolation.
