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1.
Pharmacogenomics J ; 16(2): 202-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25987242

RESUMO

The drug efflux transporter permeability glycoprotein (PGP) and cytochrome P450 (CYP) 2C19 are important for eliminating antidepressants from the brain and body. The ABCB1 gene, encoding for PGP, and CYP2C19 gene have several variants that could influence enzyme function and thereby the effect of PGP- and 2C19-dependent antidepressants. We investigated the association of antidepressant side effect and common genetic variation in 789 antidepressant users. In PGP-dependent antidepressant users, the A-allele of the rs2032588 single-nucleotide polymorphism (SNP) was associated with a lower number of side effects after adjusting for gender, age, dosage and duration of use, (B=-0.44, q=4.6 × 10(-3)). This association was different from and absent in non-PGP-dependent antidepressant users. Other SNP associations as well as an interaction analysis between the rs2032588 SNP and the CYP2C19 SNPs were not statistically significant after adjusting for covariates and multiple comparisons. The association of rs2032588 with antidepressant side effects suggests the involvement of the ABCB1 genotype in the clinical pharmacology of PGP-dependent antidepressants.


Assuntos
Antidepressivos/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Estudos de Coortes , Citocromo P-450 CYP2C19/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
2.
Mol Psychiatry ; 20(12): 1588-95, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25687773

RESUMO

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.


Assuntos
Doença de Alzheimer/genética , Doença de Parkinson/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteínas E/genética , Encéfalo/patologia , Cromossomos Humanos Par 17 , Feminino , Loci Gênicos , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
3.
BMC Med Genet ; 16: 50, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26188928

RESUMO

BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.


Assuntos
Anormalidades Congênitas/genética , Consanguinidade , Genes Recessivos , Genoma Humano/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Estatísticas não Paramétricas
4.
Clin Genet ; 85(2): 154-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23438842

RESUMO

Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.


Assuntos
Exoma/genética , Técnicas de Diagnóstico Molecular/métodos , Proteínas/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Códon sem Sentido/genética , Primers do DNA/genética , Feminino , Genes Recessivos/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA , Espanha
5.
Nat Genet ; 6(3): 287-92, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8012392

RESUMO

Triphalangeal thumb is a developmental anomaly, sometimes dominantly transmitted, characterized by a long, finger-like thumb with three phalanges instead of two. The underlying genetic defect is unknown, but presumably involves genes that regulate the differentiation of the developing forelimb. In two large kindreds with triphalangeal thumb, evidence for linkage to the long arm of chromosome 7 was obtained with a maximum lod score of 12.61. Multipoint linkage and haplotype analysis placed the gene close to the telomere of the long arm. To our knowledge this is the first time that a human gene involved solely in the pathologic morphogenesis of the hand and feet has been localized.


Assuntos
Cromossomos Humanos Par 7 , Polidactilia/genética , Polegar/anormalidades , Mapeamento Cromossômico , Feminino , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Escore Lod , Masculino , Linhagem , Polidactilia/classificação
6.
Nat Genet ; 28(3): 213-4, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11431687

RESUMO

Hereditary hemochromatosis (HH) is a very common disorder characterized by iron overload and multi-organ damage. Several genes involved in iron metabolism have been implicated in the pathology of HH (refs. 1-4). We report that a mutation in the gene encoding Solute Carrier family 11, member A3 (SLC11A3), also known as ferroportin, is associated with autosomal dominant hemochromatosis.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Hemocromatose/genética , Mutação , Sequência de Aminoácidos , Feminino , Ferritinas/sangue , Genes Dominantes , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos , Transferrina/análise
7.
Nat Genet ; 18(2): 164-7, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9462747

RESUMO

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.


Assuntos
Cromossomos Humanos Par 14 , Distrofias Musculares/genética , Proteínas de Ligação a RNA/genética , Repetições de Trinucleotídeos , Adulto , Idoso , Sequência de Bases , Canadá , Mapeamento Cromossômico , Clonagem Molecular , Feminino , França/etnologia , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Proteínas de Ligação a Poli(A) , População Branca
8.
Genes Immun ; 13(2): 197-201, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21866115

RESUMO

Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.


Assuntos
Linfoma não Hodgkin/genética , Polimorfismo Genético , Receptor Toll-Like 9/genética , Feminino , Genética Populacional , Humanos , Linfoma não Hodgkin/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
9.
Mol Psychiatry ; 14(4): 359-75, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19065144

RESUMO

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.


Assuntos
Proteínas do Citoesqueleto/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Neuropeptídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade
10.
Eur J Neurol ; 16(3): 297-309, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19364361

RESUMO

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.


Assuntos
Transtornos Parkinsonianos/complicações , Tauopatias/complicações , Animais , Biomarcadores , Demência/complicações , Demência/genética , Demência/fisiopatologia , Desenho de Fármacos , Geografia , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Modelos Biológicos , Mutação , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/fisiopatologia , Doença de Parkinson Pós-Encefalítica/complicações , Doença de Parkinson Pós-Encefalítica/fisiopatologia , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/terapia , Doença de Pick/complicações , Doença de Pick/patologia , Proteínas Serina-Treonina Quinases/genética , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/fisiopatologia , Tauopatias/patologia , Tauopatias/fisiopatologia , Tauopatias/terapia , Proteínas tau/genética
12.
J Med Genet ; 43(6): 490-5, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16107487

RESUMO

BACKGROUND: Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents from various causes. Several familial cases have been described and autosomal dominant inheritance linked to chromosome 13q has been suggested. COL4A1 is an essential component in basal membrane stability. Mouse mutants bearing an in-frame deletion of exon 40 of Col4a1 either die from haemorrhage in the perinatal period or have porencephaly in survivors. A report of inherited mutations in COL4A1 in two families has shown that familial porencephaly may have the same cause in humans. OBJECTIVE: To describe three novel COL4A1 mutations. RESULTS: The three mutations occurred in three unrelated Dutch families. There were two missense mutations of glycine residues predicted to result in abnormal collagen IV assembly, and one mutation predicted to abolish the traditional COL4A1 start codon. The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain magnetic resonance imaging. CONCLUSIONS: This observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral haemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.


Assuntos
Encefalopatias/genética , Colágeno Tipo IV/genética , Adulto , Encefalopatias/diagnóstico , Encefalopatias/patologia , Criança , Pré-Escolar , Colágeno Tipo IV/química , Colágeno Tipo IV/fisiologia , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Estrutura Terciária de Proteína
13.
J Med Genet ; 43(7): e35, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16816022

RESUMO

We report on a multigenerational family with isolated Hirschsprung's disease (HSCR). Five patients were affected by either short segment or long segment HSCR. The family consists of two main branches: one with four patients (three siblings and one maternal uncle) and one with one patient. Analysis of the RET gene, the major gene involved in HSCR susceptibility, revealed neither linkage nor mutations. A genome wide linkage analysis was performed, revealing suggestive linkage to a region on 4q31-q32 with a maximum parametric multipoint LOD score of 2.7. Furthermore, non-parametric linkage (NPL) analysis of the genome wide scan data revealed a NPL score of 2.54 (p = 0.003) for the same region on chromosome 4q (D4S413-D4S3351). The minimum linkage interval spans a region of 11.7 cM (12.2 Mb). No genes within this chromosomal interval have previously been implicated in HSCR. Considering the low penetrance of disease in this family, the 4q locus may be necessary but not sufficient to cause HSCR in the absence of modifying loci elsewhere in the genome. Our results suggest the existence of a new susceptibility locus for HSCR at 4q31.3-q32.3.


Assuntos
Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Doença de Hirschsprung/genética , Mapeamento Cromossômico , Feminino , Genes Dominantes , Humanos , Masculino , Países Baixos , Linhagem , Proteínas Proto-Oncogênicas c-ret/genética
14.
Ned Tijdschr Geneeskd ; 151(30): 1665-8, 2007 Jul 28.
Artigo em Holandês | MEDLINE | ID: mdl-17725253

RESUMO

In recent years, 5 genes have been identified that are unambiguously associated with genetic forms of Parkinson's disease. These genes probably explain less than 10% of all cases of Parkinson's disease. Clinically, these genetic forms can closely resemble idiopathic Parkinson's disease. Mutation analysis could be considered in cases involving an age at onset before 45 years, a positive family history or atypical presentations. However, the role of genetic testing in clinical practice remains to be established. Dysfunction of the ubiquitin-proteasome complex, abnormalities of the oxidative stress response and mitochondrial defects represent the three main disease mechanisms implicated in Parkinson's disease caused by these gene mutations. Further research is likely to contribute to the understanding and future treatment of idiopathic Parkinson's disease.


Assuntos
Doença de Parkinson/genética , Família , Humanos , Doenças Mitocondriais/genética , Mutação , Ubiquitina-Proteína Ligases/genética
15.
Genes Brain Behav ; 5 Suppl 2: 25-33, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16681798

RESUMO

Psychiatric disorders place a large burden not only on affected individuals and their families but also on societies and health services. Current treatment is only effective in a proportion of the patients, so considerable effort has been put into the development of new medications. The susceptibility to all major psychiatric disorders is, at least in part, genetic. Knowledge of the genes that underlie this susceptibility may lead to the identification of new drug targets and the development of more effective treatments. Therefore, numerous genetic studies in search for the genes involved in psychiatric disorders have been performed. Although results of both linkage and association studies have been inconsistent, several promising gene regions and candidate genes have been identified recently. In this article, we will review the strategies that proved to be successful in detecting genes for psychiatric disorders and we will provide some recommendations to increase the probability of detecting susceptibility genes in genetic studies of different designs.


Assuntos
Predisposição Genética para Doença , Transtornos Mentais/genética , Fenótipo , Determinismo Genético , Ligação Genética , Marcadores Genéticos , Humanos
16.
Genes Brain Behav ; 5(8): 577-84, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17081262

RESUMO

The CHRM2 gene is thought to be involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release and has previously been implicated in higher cognitive processing. In a sample of 667 individuals from 304 families, we genotyped three single-nucleotide polymorphisms (SNPs) in the CHRM2 gene on 7q31-35. From all individuals, standardized intelligence measures were available. Using a test of within-family association, which controls for the possible effects of population stratification, a highly significant association was found between the CHRM2 gene and intelligence. The strongest association was between rs324650 and performance IQ (PIQ), where the T allele was associated with an increase of 4.6 PIQ points. In parallel with a large family-based association, we observed an attenuated - although still significant - population-based association, illustrating that population stratification may decrease our chances of detecting allele-trait associations. Such a mechanism has been predicted earlier, and this article is one of the first to empirically show that family-based association methods are not only needed to guard against false positives, but are also invaluable in guarding against false negatives.


Assuntos
Variação Genética , Inteligência/genética , Receptor Muscarínico M2/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 7/genética , Feminino , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Linhagem , Polimorfismo de Nucleotídeo Único , Gêmeos Dizigóticos , Gêmeos Monozigóticos
17.
J Neural Transm Suppl ; (70): 215-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17017532

RESUMO

Our genetic knowledge of Parkinson's disease (PD) is moving forward at an impressive speed. In less then 10 years family-based linkage analysis and positional cloning have led to the identification of several genes for familial forms of PD, which has been of critical importance to the scientific advance of PD research as the causal genes have offered new tools to model and understand pathways leading to neurodegeneration in PD.


Assuntos
Genes Recessivos/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Oncogênicas/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Humanos , Proteína Desglicase DJ-1
18.
Brain ; 128(Pt 11): 2645-53, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16014652

RESUMO

Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found in a family with hereditary Pick's disease with the G272V mutation and in several families with other tau mutations in exons 9 and 11-13. The biochemical composition of Pick bodies varies between these mutations. Until recently, no detailed biochemical characterization of G272V brain material was done owing to unavailability of fresh frozen brain material. We now report a detailed study using the immunohistochemistry, western blots and electron microscopy of two brains with the G272V mutation that recently became available. Both brains showed severe neuronal loss in the temporal cortex, whereas in the frontal cortex the loss was less; and abundant Pick bodies in the dentate gyrus of the hippocampus, and caudate nucleus. The Pick bodies consisted exclusively of three-repeat (3R) isoforms, as was demonstrated by isoform-specific antibodies and supported by western blot analysis of sarkosyl-insoluble tau. These observations confirm that this family diagnosed with hereditary Pick disease meets all the criteria for this condition, including the presence of Pick bodies that are unphosphorylated at Ser262 and contain twisted filaments with long periodicity consisting only of 3R tau.


Assuntos
Mutação , Proteínas do Tecido Nervoso/genética , Doença de Pick/genética , Proteínas tau/genética , Western Blotting , Cromossomos Humanos Par 17/genética , Análise Mutacional de DNA , Feminino , Lobo Frontal/ultraestrutura , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Doença de Pick/metabolismo , Doença de Pick/patologia , Proteínas tau/metabolismo
19.
Neurobiol Aging ; 48: 222.e1-222.e7, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27640074

RESUMO

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Melanoma/genética , Doença de Parkinson/genética , Neoplasias Cutâneas/genética , Estudos de Coortes , Receptor DCC , Dopamina/biossíntese , Genótipo , Humanos , Melaninas/biossíntese , Glicoproteínas de Membrana/genética , Monofenol Mono-Oxigenase , Oxirredutases/genética , Pigmentação/genética , Receptor ErbB-4/genética , Receptores de Superfície Celular/genética , Risco , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
20.
Diabetes ; 50(3): 637-42, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11246885

RESUMO

Evidence is accumulating that low levels of IGF-I play a role in the pathogenesis of type 2 diabetes and cardiovascular diseases. We examined the role of a genetic polymorphism in the promoter region of the IGF-I gene in relation to circulating IGF-I levels and growth measured as body height, and we studied the relationship of this polymorphism with type 2 diabetes and myocardial infarction. The relation between the IGF-I polymorphism and body height was assessed in a population-based sample of 900 subjects from the Rotterdam Study. Within each genotype stratum, 50 subjects were randomly selected for a study of the relation of this polymorphism with serum IGF-I levels. To assess the risk for type 2 diabetes, we studied 220 patients and 596 normoglycemic control subjects. For myocardial infarction, 477 patients with evidence of myocardial infarction on electrocardiogram and 808 control subjects were studied. A 192-bp allele was present in 88% of the population, suggesting that this is the wild-type allele from which all other alleles originated. Body height was, on average, 2.7 cm lower (95% CI for difference -4.6 to -0.8 cm, P = 0.004), and serum IGF-I concentrations were 18% lower (95% CI for difference -6.0 to -1.3 mmol/l, P = 0.003) in subjects who did not carry the 192-bp allele. In noncarriers of the 192-bp allele, an increased relative risk for type 2 diabetes (1.7 [95% CI 1.1-2.7]) and for myocardial infarction (1.7 [95% CI 1.1-2.5]) was found. In patients with type 2 diabetes, the relative risk for myocardial infarction in subjects without the 192-bp allele was 3.4 (95% CI 1.1-11.3). Our study suggests that a genetically determined exposure to relatively low IGF-I levels is associated with an increased risk for type 2 diabetes and myocardial infarction.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Fator de Crescimento Insulin-Like I/genética , Infarto do Miocárdio/genética , Polimorfismo Genético , Idoso , Alelos , Estatura , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/fisiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Polimorfismo Genético/fisiologia , Regiões Promotoras Genéticas/genética , Valores de Referência
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