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1.
Genes Immun ; 17(5): 305-12, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27278126

RESUMO

To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on the significance of linkage disequilibrium blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery. The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P=6.1E-15, 1.2E-14 and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Loci Gênicos , Ativação Linfocitária/genética , Esclerose Múltipla/genética , NF-kappa B/metabolismo , Transdução de Sinais/genética , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , NF-kappa B/genética
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.
Hum Genet ; 132(11): 1213-21, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23793441

RESUMO

Previous evidence has shown that Parkinson disease (PD) has a heritable component, but only a small proportion of the total genetic contribution to PD has been identified. Genetic heterogeneity complicates the verification of proposed PD genes and the identification of new PD susceptibility genes. Our approach to overcome the problem of heterogeneity is to study a population isolate, the mid-western Amish communities of Indiana and Ohio. We performed genome-wide association and linkage analyses on 798 individuals (31 with PD), who are part of a 4,998 member pedigree. Through these analyses, we identified a region on chromosome 5q31.3 that shows evidence of association (p value < 1 × 10(-4)) and linkage (multipoint HLOD = 3.77). We also found further evidence of linkage on chromosomes 6 and 10 (multipoint HLOD 4.02 and 4.35 respectively). These data suggest that locus heterogeneity, even within the Amish, may be more extensive than previously appreciated.


Assuntos
Amish/genética , Loci Gênicos , Doença de Parkinson/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 6/genética , Biologia Computacional , Ligação Genética , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Indiana , Ohio , Linhagem , Polimorfismo de Nucleotídeo Único
4.
Semin Immunol ; 21(6): 328-33, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19775910

RESUMO

Multiple sclerosis (MS) is an idiopathic autoimmune neurodegenerative disease. Like many common diseases, MS has a genetic component; however, as with most complex diseases, the genetic architecture may be influenced by heterogeneity, incomplete penetrance, polygenic inheritance, and environmental factors. This clinically complex disease has provided great challenges for geneticists over the years. Although the first consistent genetic association to MS (with HLA-DR*1501) was discovered more than 30 years ago, lack of consistently replicated genetic results has plagued the scientific community. New study design methods (particularly genome-wide associations studies [GWAS]) along with genome project data and larger datasets have allowed several additional MS genes to be identified and consistently replicated. Thus, after many years of frustration, the strong genetic component associated with MS is finally beginning to be characterized.


Assuntos
Esclerose Múltipla/genética , Animais , Estudo de Associação Genômica Ampla , Humanos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia
5.
Nat Genet ; 7(4): 521-4, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7951323

RESUMO

Haw River Syndrome (HRS) is a dominant neurodegenerative disease that has affected five generations of an African-American family in rural North Carolina. The disorder represents a unique spectrum of multiple system degenerations resembling Huntington's disease, spinocerebellar atrophy and dentatorubropallidoluysian atrophy (DRPLA), a neurodegenerative disease that has been primarily reported in Japan. Recently, DRPLA has been shown to be due to an expanded trinucleotide repeat located on chromosome 12pter-p12. We have genotyped this family and found HRS to be tightly linked to the DRPLA region. Further examination demonstrates that, despite their distinct cultural origins and clinical and pathological differences, HRS is caused by the same expanded CTG-B37 repeat as DRPLA.


Assuntos
Encefalopatias/genética , Atrofia , População Negra/genética , Encefalopatias/patologia , Calcinose/genética , Núcleos Cerebelares/patologia , Cromossomos Humanos Par 12 , Feminino , Ligação Genética , Globo Pálido/patologia , Humanos , Masculino , Repetições Minissatélites , North Carolina , Oligodesoxirribonucleotídeos/genética , Linhagem , Núcleo Rubro/patologia , Sequências Repetitivas de Ácido Nucleico , Síndrome
6.
Nat Genet ; 7(3): 425-8, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7920663

RESUMO

Amyotrophic lateral sclerosis (ALS) usually presents as a sporadic disorder of motor neurons. However, familial forms of ALS have been described--autosomal dominant forms (ALS1, ALS3), clinically indistinguishable from the sporadic form, and autosomal recessive forms with early onset and slower progression of symptoms (ALS2). To localize the gene for one of the autosomal recessive forms of ALS, we applied linkage analysis to a large inbred family from Tunisia. A lod score maximum of Zmax = 8.2 at theta = 0.00 was obtained with marker D2S72 located on chromosome 2q33-q35. The fine mapping of this region suggested that the ALS2 locus lies in the 8 cM segment flanked by D2S155 and D2S115.


Assuntos
Esclerose Lateral Amiotrófica/genética , Cromossomos Humanos Par 2/genética , Genes Recessivos , Adolescente , Adulto , Esclerose Lateral Amiotrófica/classificação , Criança , Pré-Escolar , Mapeamento Cromossômico , Consanguinidade , Feminino , Marcadores Genéticos , Haplótipos/genética , Humanos , Escore Lod , Masculino , Linhagem , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Sequências Repetitivas de Ácido Nucleico , Tunísia/epidemiologia
7.
Nat Genet ; 2(4): 315-7, 1992 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-1303286

RESUMO

Autosomal recessive Duchenne-like muscular dystrophy (DLMD) is a severe dystrophic myopathy. The incidence is unknown because of its clinical similarity to Duchenne muscular dystrophy (DMD). Three highly inbred DLMD families from Tunisia were analysed for chromosomal linkage using 135 polymorphic microsatellite markers. A significant lod score of z = 9.15 at theta = 0.03 was found with the 13q12 locus D13S115. Two additional 13q12 markers, D13S143 and D13S120, also gave significant lod scores. Therefore, the primary DLMD defect gene lies in the pericentrometric region of chromosome 13q.


Assuntos
Cromossomos Humanos Par 13 , Ligação Genética , Distrofias Musculares/genética , Centrômero/ultraestrutura , Mapeamento Cromossômico , Cromossomos Humanos Par 13/ultraestrutura , Consanguinidade , DNA Satélite/genética , Feminino , Genes Recessivos , Marcadores Genéticos , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo Genético , Tunísia
8.
Nat Genet ; 29(1): 23-4, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11528386

RESUMO

A C-->G nucleotide transition in exon 4 of PTPRC (encoding protein-tyrosine phosphatase receptor-type C, also known as CD45) was recently reported to be genetically associated with the development of multiple sclerosis (MS). We performed an extensive evaluation of this polymorphism using large family-based and case-control comparisons. Overall, we observed no evidence of genetic association between the PTPRC polymorphism and MS susceptibility or disease course.


Assuntos
Antígenos Comuns de Leucócito/genética , Esclerose Múltipla/genética , Adulto , Estudos de Casos e Controles , Cromossomos Humanos Par 1 , Éxons , Feminino , Humanos , Masculino , Mutação Puntual , Polimorfismo Genético , Estados Unidos
9.
Nat Genet ; 28(2): 119-20, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11381253

RESUMO

Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.


Assuntos
Coreia/genética , Mutação , Proteínas/genética , Proteínas de Saccharomyces cerevisiae , Processamento Alternativo , Animais , Caenorhabditis elegans/genética , Linhagem Celular , Cromossomos Humanos Par 6 , Eritrócitos/fisiologia , Éxons , Proteínas Fúngicas/genética , Regulação da Expressão Gênica , Haplótipos , Humanos , Linhagem , Transporte Proteico , Proteínas/metabolismo , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Proteínas de Transporte Vesicular
10.
Nat Genet ; 13(2): 189-95, 1996 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8640225

RESUMO

Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1), a member of the serine-threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.


Assuntos
Cromossomos Humanos Par 12 , Mutação , Proteínas Serina-Treonina Quinases/genética , Telangiectasia Hemorrágica Hereditária/genética , Receptores de Ativinas , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Telangiectasia Hemorrágica Hereditária/classificação
11.
Nat Genet ; 29(2): 160-5, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11586297

RESUMO

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).


Assuntos
Esclerose Lateral Amiotrófica/genética , Genes Recessivos , Fatores de Troca do Nucleotídeo Guanina/genética , Mutação , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , Primers do DNA , Feminino , Ligação Genética , Fatores de Troca do Nucleotídeo Guanina/química , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Transdução de Sinais
12.
Nat Genet ; 13(4): 469-71, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8696344

RESUMO

Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).


Assuntos
Cromossomos Humanos Par 6 , Complexo Principal de Histocompatibilidade , Esclerose Múltipla/genética , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 7/genética , Ligação Genética , Marcadores Genéticos , Humanos , Linhagem
13.
Nat Genet ; 2(4): 330-4, 1992 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-1303289

RESUMO

Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.


Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Par 14 , Idoso , Alelos , Precursor de Proteína beta-Amiloide/genética , Sequência de Bases , Mapeamento Cromossômico , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem
14.
Clin Genet ; 79(6): 523-30, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20718791

RESUMO

Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. Over 40 chromosomal loci have been identified for autosomal dominant, recessive, and X-linked HSP. Mutations in the genes atlastin, spastin and REEP1 are estimated to account for up to 50% of autosomal-dominant HSP and currently guide the molecular diagnosis of HSP. Here, we report the mutation screening results of 120 HSP patients from North America for spastin, atlastin, and REEP1, with the latter one partially reported previously. We identified mutations in 36.7% of all tested HSP patients and describe 20 novel changes in spastin and atlastin. Our results add to a growing number of HSP disease-associated variants and confirm the high prevalence of atlastin, spastin, and REEP1 mutations in the HSP patient population.


Assuntos
Adenosina Trifosfatases/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana Transportadoras/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Proteínas de Ligação ao GTP , Genes Dominantes , Genes Recessivos , Marcadores Genéticos , Testes Genéticos , Humanos , Mutação INDEL , Lactente , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Espastina , Adulto Jovem
15.
Genes Immun ; 11(8): 660-4, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20574445

RESUMO

Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10⁻6) in MS susceptibility.


Assuntos
ATP Citrato (pro-S)-Liase/genética , Calicreínas/genética , Esclerose Múltipla/genética , Neprilisina/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Proteínas de Ciclo Celular , Mapeamento Cromossômico , Proteínas do Citoesqueleto , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação
16.
Am J Med Genet B Neuropsychiatr Genet ; 153B(2): 477-483, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-19588468

RESUMO

Autism is a heritable neurodevelopmental disorder with substantial genetic heterogeneity. Studies point to possible links between autism and two serotonin related genes: SLC6A4 and ITGB3 with a sex-specific genetic effect and interaction between the genes. Despite positive findings, inconsistent results have complicated interpretation. This study seeks to validate and clarify previous findings in an independent dataset taking into account sex, family-history (FH) and gene-gene effects. Family-based association analysis was performed within each gene. Gene-gene interactions were tested using extended multifactor dimensionality reduction (EMDR) and MDR-phenomics (MDR-P) using sex of affecteds and FH as covariates. No significant associations with individual SNPs were found in the datasets stratified by sex, but associations did emerge when we stratified by family history. While not significant in the overall dataset, nominally significant association was identified at RS2066713 (P = 0.006) within SLC6A4 in family-history negative (FH-) families, at RS2066713 (P = 0.038) in family-history positive (FH+) families but with the opposite risk allele as in the FH- families. For ITGB3, nominally significant association was identified at RS3809865 overall (P = 0.040) and within FH+ families (P = 0.031). However, none of the associations survived the multiple testing correction. MDR-P confirmed gene-gene effects using sex of affecteds (P = 0.023) and family history (P = 0.014, survived the multiple testing corrections) as covariates. Our results indicate the extensive heterogeneity within these two genes among families. The potential interaction between SLC6A4 and ITGB3 may be clarified using family history as an indicator of genetic architecture, illustrating the importance of covariates as markers of heterogeneity in genetic analyses.


Assuntos
Transtorno Autístico/genética , Integrina beta3/genética , Modelos Genéticos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Alelos , Saúde da Família , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
17.
Genes Immun ; 10(7): 624-30, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19626040

RESUMO

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disease affecting >4,00,000 individuals in the United States. Population and family-based studies have suggested that there is a strong genetic component. Numerous genomic linkage screens have identified regions of interest for MS loci. Our own second-generation genome-wide linkage study identified a handful of non-major histocompatibility complex regions with suggestive linkage. Several of these regions were further examined using single-nucleotide polymorphisms (SNPs) with average spacing between SNPs of approximately 1.0 Mb in a dataset of 173 multiplex families. The results of that study provided further evidence for the involvement of the chromosome 1q43 region. This region is of particular interest given linkage evidence in studies of other autoimmune and inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus. In this follow-up study, we saturated the region with approximately 700 SNPs (average spacing of 10 kb per SNP) in search of disease-associated variation within this region. We found preliminary evidence to suggest that common variation within the RGS7 locus may be involved in disease susceptibility.


Assuntos
Cromossomos Humanos Par 1/genética , Ligação Genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Proteínas RGS/genética , Alelos , Feminino , Seguimentos , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
18.
Neurogenetics ; 10(3): 209-16, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19184136

RESUMO

Autism is characterized as one of the pervasive developmental disorders, a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-hydroxytryptamine) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 single nucleotide polymorphisms in ten serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p = 0.0002; p = 0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on chromosome 11 ( approximately 113 Mb). To test specifically for multilocus effects, multifactor dimensionality reduction was employed, and a significant two-way interaction (p value = 0.01) was found between rs10830962, near MTNR1B (chromosome11; 92,338,075 bp), and rs1007631, near SLC7A5 (chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk.


Assuntos
Transtorno Autístico/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Serotonina/genética , Adolescente , Criança , Pré-Escolar , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Estrutura Molecular , Serotonina/química , Serotonina/metabolismo , Triptofano/química , Triptofano/metabolismo , Adulto Jovem
19.
Science ; 261(5123): 921-3, 1993 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-8346443

RESUMO

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.


Assuntos
Alelos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Frequência do Gene , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Doença de Alzheimer/metabolismo , Doença de Alzheimer/mortalidade , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4 , Apolipoproteínas E/fisiologia , Feminino , Genótipo , Homozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Fatores de Risco , Taxa de Sobrevida
20.
Science ; 235(4796): 1648-50, 1987 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-3029876

RESUMO

Myotonic muscular dystrophy (DM) is the most common muscular dystrophy, affecting adults as well as children. It is inherited as an autosomal dominant trait and is characterized by variable expressivity and late age-of-onset. Linkage studies have established the locus on chromosome 19. In order to identify tightly linked probes for diagnosis as well as to define in detail the DM gene region, chromosome 19 libraries were constructed and screened for restriction fragment length polymorphisms tightly linked to DM. A genomic clone, LDR152 (D19S19), was isolated that is tightly linked to DM; recombination fraction = 0.0 (95% confidence limits 0.0-0.03); lod score, 15.4.


Assuntos
Distrofias Musculares/diagnóstico , Adulto , Autorradiografia , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Enzimas de Restrição do DNA/metabolismo , Ligação Genética , Humanos , Distrofias Musculares/genética , Linhagem , Polimorfismo Genético
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