ABSTRACT
We performed detailed clinical, histopathological, biochemical, in vitro translation and molecular genetic analysis in patients from two unrelated families harbouring the tRNA(SerUCN) 7472C-insertion mutation. Proband 1 developed a progressive neurodegenerative phenotype characterised by myoclonus, epilepsy, cerebellar ataxia and progressive hearing loss. Proband 2 had a comparatively benign phenotype characterised by isolated myopathy with exercise intolerance. Both patients had the 7472C-insertion mutation in identical proportions and they exhibited a similar muscle biochemical and histopathological phenotype. However, proband 2 also had a previously unreported homoplasmic A to C transition at nucleotide position 7472 in the tRNA(SerUCN) gene. This change lengthens further the homopolymeric C run already expanded by the 7472C-insertion. These data extend the phenotypic range associated with the 7472C-insertion to include isolated skeletal myopathy, as well as a MERRF-like phenotype.
Subject(s)
DNA, Mitochondrial/genetics , Mitochondrial Encephalomyopathies/genetics , Mutation , RNA, Transfer, Ser/genetics , Adolescent , Adult , DNA Mutational Analysis/methods , Electron Transport Complex IV/metabolism , Electrophoresis/methods , Female , Humans , Male , Microscopy, Electron, Transmission/methods , Mitochondria, Muscle/pathology , Mitochondrial Encephalomyopathies/enzymology , Mitochondrial Encephalomyopathies/pathology , Mitochondrial Encephalomyopathies/physiopathology , Mitochondrial Proteins/metabolism , Muscle, Skeletal/enzymology , Muscle, Skeletal/pathology , Muscle, Skeletal/ultrastructure , Nucleic Acid Conformation , Phenotype , RNA, Transfer, Ser/chemistry , Serine/metabolismSubject(s)
Codon, Nonsense/genetics , DNA, Mitochondrial/genetics , Exercise Tolerance/genetics , Muscle Weakness/genetics , Muscle, Skeletal/metabolism , Muscular Diseases/genetics , DNA Mutational Analysis , Electron Transport Complex I/deficiency , Electron Transport Complex I/genetics , Energy Metabolism/genetics , Female , Genetic Predisposition to Disease/genetics , Humans , Middle Aged , Mitochondria/genetics , Mitochondria/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Muscle Weakness/metabolism , Muscle Weakness/physiopathology , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Diseases/metabolism , Muscular Diseases/physiopathology , NADH Dehydrogenase/deficiency , NADH Dehydrogenase/genetics , Ophthalmoplegia/genetics , Ophthalmoplegia/metabolism , Ophthalmoplegia/physiopathologyABSTRACT
OBJECTIVE: To test the hypothesis that polymorphic variation in insulin signalling genes may underlie the shared risk of dysfunctional insulin signalling and late onset Alzheimer's disease (AD). The p85alpha subunit of phosphatidyl inositol 3 kinase (PIK3R1) and the regulatory subunit 3 of protein phosphatase 1 (PPP1R3) were selected as candidate genes because both encode key proteins involved in insulin signalling and because polymorphisms in these genes have been previously implicated in insulin resistance or type II diabetes. METHODS: Analysis of the Met326Ile PIK3R1 and the Asp905Tyr PPP1R3 polymorphisms in 202 patients with late onset AD and 160 or 170 age matched normal subjects. RESULTS: Logistic regression analysis using the recessive genetic model showed significant differences in genotype and allelic frequencies between the AD group and normal controls (genotypes: odds ratio (OR) 2.09, 95% confidence interval (CI) 1.17 to 3.74, p = 0.01; alleles: OR 1.99, 95% CI 1.17 to 3.40, p = 0.01) for the Met326Ile PIK3R1 polymorphism that were female specific. Additionally, in the dominant genetic model a marginally significant association in genotype frequencies between the Asp905Tyr PPP1R3 polymorphism and AD was observed (genotypes: OR 1.85, 95% CI 1.03 to 3.30, p = 0.04; alleles: OR 1.68, 95% CI 0.98 to 2.88, p = 0.06). Both polymorphisms were tested for their interactions with sex and the presence of the apolipoprotein E epsilon 4 allele. CONCLUSIONS: The results support the hypothesis for a common genetic aetiology predisposing to insulin resistance and AD.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Insulin Resistance/genetics , Insulin/metabolism , Age Factors , Aged , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Female , Gene Frequency , Genotype , Humans , Male , Phosphatidylinositol 3-Kinases/genetics , Phosphoprotein Phosphatases/genetics , Polymorphism, Genetic/genetics , Protein Phosphatase 1 , Risk FactorsABSTRACT
BACKGROUND: Serotonin dysfunction has been implicated in hypertension due to its ability to induce vasoconstriction via stimulation of 5-HT(2) receptors and due to the antihypertensive effect of ketanserin, an antagonist at the 5-HT(2A) receptor subtype, expressed both on arteries and the brain. The silent T102C polymorphism in the 5-HT(2A) gene is in absolute linkage disequilibrium with a polymorphism in the promoter and may contribute to genetic predisposition possibly by modifying the transcription of the gene. OBJECTIVE: To examine the genetic contribution of the T102C 5-HT(2A)polymorphism in essential hypertension in a case-control sample of UK residents. DESIGN: The hypertensive group consisted of 342 subjects over 75 years and the community-based control group consisted of 319 subjects. Subjects were genotyped for the T102C polymorphism by Mspl restriction enzyme digestion following PCR amplification. RESULTS: Sex-specific association analysis revealed significant differences between hypertensive and normotensive subjects in the genotypes distribution (P = 0.016) and allelic frequencies (P = 0.007) in the female group. The direction of significance was increased frequency of the 102-C allele in the hypertensive subjects. There were no association between haplotype and age or body mass index, which suggest that the effect of the T102C variant is not influenced by these variables. CONCLUSION: This data indicates that the T102C polymorphism in the 5-HT(2A) gene might be an independent risk factor for increased blood pressure in female individuals with essential hypertension.
Subject(s)
Genetic Testing , Hypertension/genetics , Polymorphism, Genetic , Receptors, Serotonin/genetics , Age Distribution , Aged , Aged, 80 and over , Alleles , Chi-Square Distribution , Female , Gene Expression , Genetic Linkage , Genetic Predisposition to Disease/epidemiology , Genotype , Humans , Hypertension/diagnosis , Hypertension/epidemiology , Male , Probability , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/analysis , Sensitivity and Specificity , Sex Distribution , United Kingdom/epidemiologyABSTRACT
Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.
Subject(s)
Alzheimer Disease/genetics , Insulysin/genetics , Linkage Disequilibrium , Age of Onset , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/etiology , Case-Control Studies , Genetic Variation , Humans , Polymorphism, Single Nucleotide , White PeopleABSTRACT
AIMS: We set out to examine the evidence for an association between cognitive impairment or dementia and the presence of Type 2 diabetes mellitus (DM). We also sought evidence of potential mechanisms for such an association. METHODS: A literature search of three databases was performed and the reference lists of the papers so identified were examined, using English language papers only. RESULTS: We found evidence of cross-sectional and prospective associations between Type 2 DM and cognitive impairment, probably both for memory and executive function. There is also evidence for an elevated risk of both vascular dementia and Alzheimer's disease in Type 2 DM albeit with strong interaction of other factors such as hypertension, dyslipidaemia and apolipoprotein E phenotype. Both vascular and non-vascular factors are likely to play a role in dementia in diabetes. CONCLUSIONS: Current classification structures for dementia may not be adequate in diabetes, where mixed pathogenesis is likely. Further research into the mechanisms of cognitive impairment in Type 2 DM may allow us to challenge the concept of dementia, at least in these patients, as an irremediable disease.
