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1.
Cancer Res ; 57(5): 842-5, 1997 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-9041183

RESUMO

Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin's syndrome, is an autosomal dominant disorder that predisposes to developmental defects and various forms of cancer. PTCH was recently proposed as a candidate gene for NBCCS due to its frequent mutation in basal cell carcinomas, the cancer most often associated with this syndrome. Another NBCCS-associated cancer is medulloblastoma, a common central nervous system tumor in children. Most medulloblastomas, however, occur without indication of an inherited predisposition. We have examined 24 sporadic medulloblastomas for loss of heterozygosity (LOH) at loci flanking as well as within PTCH. In cases with LOH, single-strand conformational polymorphism and sequencing analysis were performed to determine the status of the remaining PTCH allele. Microsatellite analysis indicated LOH of PTCH in 5 of 24 tumors, and in three of these cases a mutation of the remaining allele was identified. Two of the mutations were duplication insertions, and the third consisted of a single base deletion. It is interesting that all three mutations occur in exon 17 of the PTCH gene. These data suggest that inactivation of PTCH function is involved in the development of at least a subset of sporadic medulloblastomas.


Assuntos
Meduloblastoma/genética , Proteínas de Membrana/genética , Cromossomos Humanos Par 9 , Heterozigoto , Humanos , Repetições de Microssatélites , Receptores Patched , Receptor Patched-1 , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Receptores de Superfície Celular , Deleção de Sequência
2.
Neurology ; 52(7): 1500-3, 1999 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-10227645

RESUMO

We scanned for all genetic variants in functionally important regions of the tumor necrosis factor receptor 1 gene (TNF-R1) in 100 to 111 MS patients from Olmsted County, MN, and analyzed selected variants for an association with disease course and severity. Ten genetic variants were uncovered. Only one variant, a silent substitution, was found in coding sequence. One intronic variant may generate a novel splice-junction sequence. We did not find an association between either this intronic variant or another common promoter variant and the course or severity of MS.


Assuntos
Variação Genética , Esclerose Múltipla/genética , Receptores do Fator de Necrose Tumoral/genética , Mapeamento Cromossômico , Humanos , Mutação
3.
J Neuroimmunol ; 106(1-2): 220-7, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10814801

RESUMO

We studied the putative association of a C-->T polymorphism in exon-5 of IL-1beta and an 85 bp tandem repeat in intron-4 of IL-1 receptor antagonist (IL-1ra) genes with susceptibility to or outcome of MS. DNA from 122 cases from a population-based cohort in Olmsted County, MN who were previously categorized for disease severity and temporal course and 244 ethnically-matched controls were analyzed. There was no association between either polymorphism and disease susceptibility. Allele-2 of IL-1beta and allele-3 of the IL-1ra polymorphisms were associated with a favorable outcome (P=0.023 and P=0.030).


Assuntos
Variação Genética , Interleucina-1/genética , Esclerose Múltipla/genética , Sialoglicoproteínas/genética , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Índice de Gravidade de Doença
4.
J Neuroimmunol ; 105(2): 189-94, 2000 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-10742562

RESUMO

Myeloperoxidase (MPO) generates hypochlorous acid and other reactive oxygen intermediates leading to tissue damage. MPO is expressed in macrophages-microglia in multiple sclerosis (MS) lesions. A G-->A substitution that abolishes an SP1 transcription factor consensus sequence in the promoter reduces gene expression. We studied the association of the genetic variant with MS. We did not find an association with gender, age at onset, susceptibility to, or the course and severity of MS in a population-based sample of 122 patients from Olmsted County.


Assuntos
Esclerose Múltipla/genética , Peroxidase/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Adulto , Feminino , Genótipo , Humanos , Masculino , Esclerose Múltipla/etnologia
5.
J Neuroimmunol ; 105(2): 184-8, 2000 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-10742561

RESUMO

Co-stimulation of T cells by B7-1, a protein that is expressed on antigen presenting cells, favors a T helper type1 (Th1) cellular response. Th1/Th2 bias may influence disease susceptibility or course of MS. We screened the entire coding sequence as well as the 5'- and 3'-untranslated regions of the B7-1 gene using a mutation scanning technique, dideoxyfingerprinting, in DNA from 111 patients with MS from Olmsted County, Minnesota. We identified five genetic variants. None alter protein structure nor have apparent functional significance. Selected variants of sufficient frequency were tested for an association with course and severity of MS and one was tested for an association with susceptibility; none of the association tests were positive.


Assuntos
Antígeno B7-1/genética , Variação Genética , Esclerose Múltipla/genética , Regiões 3' não Traduzidas , Humanos
6.
J Neuroimmunol ; 120(1-2): 138-45, 2001 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11694328

RESUMO

Transforming growth factor beta1 (TGFbeta1) is a Th2 cytokine encoded on chromosome 19q13, a region possibly linked to multiple sclerosis (MS). TGFbeta1 exerts favorable effects on experimental allergic encephalomyelitis. We performed a comprehensive search for genetic variants in this gene in 122 population-based sporadic cases of MS. We detected six variants, including three missense variants. We tested for association of the variants with susceptibility and course of MS and for linkage and transmission disequilibrium in a family series consisting of 395 samples in 59 pedigrees. Genetic variation in TGFB1 does not appear to contribute in a major way to susceptibility to MS.


Assuntos
Cromossomos Humanos Par 19/genética , Predisposição Genética para Doença , Testes Genéticos , Variação Genética/imunologia , Esclerose Múltipla/genética , Mutação de Sentido Incorreto/genética , Fator de Crescimento Transformador beta/genética , Adulto , Éxons/genética , Feminino , Frequência do Gene/genética , Genótipo , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1
7.
Biotechniques ; 25(1): 68-72, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9668978

RESUMO

We observed an apparent series of insertions and deletions beginning 5 bp downstream of an A-->G silent transition in exon 1 of the tumor necrosis factor receptor 1 gene. The apparent sequence anomaly was observed only in individuals carrying the transition. Formamide gel electrophoresis revealed that the apparent sequence anomaly was due to compression. The compression is plausibly explained by a hairpin in the reaction products in a region of trinucleotide CAG repeats. One should suspect the presence of DNA compression when a series of deletions and insertions follows a single base pair mutation that leads to a series of trinucleotide repeats.


Assuntos
Antígenos CD/genética , DNA/química , Mutação Puntual/genética , Receptores do Fator de Necrose Tumoral/genética , Sequência de Bases , DNA/efeitos dos fármacos , DNA/genética , Primers do DNA , Nucleotídeos de Desoxiguanina/química , Nucleotídeos de Desoxiguanina/farmacologia , Conformação de Ácido Nucleico/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral
8.
Am J Med Genet ; 74(1): 44-9, 1997 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-9034005

RESUMO

The monoamine oxidase B (MAO-B) gene was examined in 100 alleles derived from 80 Caucasian, 10 African-American, 5 Asian, and 5 Native American male patients with schizophrenia to identify sequence changes that might be associated with the disease. Approximately 235 kb of genomic sequence, primarily in coding regions, were screened by dideoxy fingerprinting, a modification of single-strand conformational polymorphism (SSCP) analysis that detects virtually 100% of sequence changes [Sarkar et al. (1992): Genomics 13:441-443; Liu and Sommer (1994): PCR Methods Appl 4:97-108]. No sequence changes of likely functional significance were identified, suggesting that mutations affecting the structure of the MAO-B protein are uncommon in the general population and are unlikely to contribute significantly to the genetic predisposition to schizophrenia. Eight polymorphisms were identified in African-Americans and Native Americans, but none were identified among Caucasians. Of the eight observed polymorphisms, a set of five transitions and one microdeletion was identified within approximately 17 kb of genomic sequence in the same 3 African-American individuals, while the remaining 7 African-Americans had a sequence identical to that in Caucasians. The presence of two such haplotypes, without intermediates, is compatible with the hypothesis that germline mutations can occur in clusters, as also suggested by other recent findings.


Assuntos
População Negra/genética , Monoaminoxidase/genética , Polimorfismo Genético , Esquizofrenia/genética , Primers do DNA/química , Ligação Genética , Marcadores Genéticos , Humanos , Indígenas Norte-Americanos/genética , Masculino , Mutação/genética , Polimorfismo Conformacional de Fita Simples , Esquizofrenia/enzimologia , Análise de Sequência , Cromossomos Sexuais , População Branca/genética
9.
Neurology ; 77(12): 1149-55, 2011 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-21900637

RESUMO

OBJECTIVE: Autoantibodies to aquaporin-4 (AQP4) are specific and pathogenic for neuromyelitis optica (NMO). Therefore, we evaluated whether AQP4 single-nucleotide polymorphisms (SNPs) are associated with susceptibility to NMO or whether mutations that potentially alter AQP4 structure or expression are present in some patients. METHODS: We genotyped 8 AQP4 SNPs chosen based on their minor allele frequency, location, and novelty in 177 NMO sporadic cases, 14 NMO familial cases, and 1,363 matched controls by TaqMan-based assay. We performed bidirectional sequencing of the promoter (1 kb), exons 0-4, and flanking splice consensus sequences, and the 5' and 3' untranslated regions of 177 sporadic and 14 familial NMO cases. RESULTS: One of 8 SNPs (minor allele frequency = 0.01) was associated with NMO (NC 18.8; chrom pos. 22695167: T>A): odds ratio (95% confidence interval) = 13.1 (1.4-126.7); p = 0.026. In 3 patients with NMO (2 related), we detected 2 different missense allelic mutations at Arg19 (R19I and R19T). None of the 1,363 control subjects had Arg19 mutations (p = 0.001). CONCLUSIONS: Except for one uncommon SNP, no tested SNP was associated with NMO, nor were 3 SNP haplotypes, providing no support for the hypothesis that genetic variation in AQP4 accounts for overall susceptibility to NMO. Two different allelic Arg19 missense mutations are specific to NMO and segregated with the disease in one pedigree. Although the pathobiology underlying this is not yet established, their effects on the structure of the M1 isoform N terminus or the regulatory sequence of the M23 isoform by virtue of their location support a role of AQP4 orthogonal array formation on molecular susceptibility to NMO.


Assuntos
Aquaporina 4/genética , Estudo de Associação Genômica Ampla/métodos , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/genética , Adolescente , Adulto , Idoso , Aquaporina 4/imunologia , Autoanticorpos/biossíntese , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
11.
Genes Immun ; 6(2): 153-61, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15674394

RESUMO

Interferon-gamma (IFNgamma) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNgamma expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1(761)*CAn], a single nucleotide polymorphism 3' of IFNG [3'(325)*G --> A] and three flanking microsatellite markers spanning a 118 kb region around IFNG. Men carriers of the 3'(325)*A allele have increased susceptibility to MS compared to noncarriers in the USA (P=0.044; OR: 2.58, 95% CI: 0.97-8.08) and Northern Ireland (P=0.019; OR: 2.37, 95% CI: 1.10-5.13). There is a nonsignificant trend in the same direction in Belgian men (P=0.299; OR: 1.50, 95% CI: 0.71-3.26). Men carriers of I1(761)*CA13, which is in strong linkage disequilibrium with the 3'(325)*A, have increased susceptibility (P=0.050; OR: 2.22, 95% CI: 0.98-5.40), while men carriers of I1(761)*CA12 have decreased susceptibility (P=0.022; OR: 0.46, 95% CI: 0.23-0.90) to MS in the USA. Similar associations were reported in Sardinia between the I1(761)*CA12 allele and reduced risk of MS in men. Flanking markers were not associated with MS susceptibility. Polymorphisms of IFNG may contribute to differences in susceptibility to MS between men and women.


Assuntos
Predisposição Genética para Doença , Interferon gama/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Região 3'-Flanqueadora/genética , Adulto , Repetições de Dinucleotídeos/genética , Feminino , Ligação Genética , Humanos , Íntrons/genética , Masculino , Fatores Sexuais
12.
Neurogenetics ; 3(3): 159-62, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11523567

RESUMO

Pleomorphic xanthoastrocytoma (PXA) is a rare, superficially situated tumor that most frequently occurs in the temporal lobe of young adults and is often associated with seizures. It generally has a relatively favorable prognosis. Prior studies have shown that TP53 mutations may occur in up to 25% of PXAs, suggesting that PXA may have an etiology similar to diffuse astrocytoma rather than pilocytic astrocytoma. In the present study, we performed immunostaining for p53 protein and examined the mutation status of exons 5-8 of the p53 gene in 55 PXAs, 8 of which had undergone one or multiple recurrences. Of 55 primary PXAs, 35 (64%) showed staining in <1% of tumor cells, 15 (27%) in 1-10%, 4 (7%) in 11-50%, and only 1 (2%) in >50%. No significant increase in p53 protein expression was noted in recurrences, even when associated with increased histological anaplasia. We found a TP53 heterozygous mutation in exon 7 in 1 of 47 primary tumors that yielded useable DNA, and in its recurrence 3 years later. This tumor, a grade II PXA, did not show signs of anaplastic transformation at recurrence. Eleven additional recurrences from 7 patients, 5 of which showed signs of histological anaplasia, did not show TP53 mutations in exons 5-8. Based on our data, the p53 mutation appears to be an uncommon (2%) genetic event in PXA formation and does not appear to be involved in tumor progression. Consequently, our findings suggest that the genetic events that underlie PXA formation differ from those involved in diffuse astrocytoma.


Assuntos
Astrocitoma/genética , Mutação , Proteína Supressora de Tumor p53/genética , Éxons , Heterozigoto , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase , Proteína Supressora de Tumor p53/análise
13.
Neurology ; 62(5): 811-4, 2004 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-15007140

RESUMO

The authors studied the association of an exon 4 (E4*epsilon2/3/4) and three promoter polymorphisms of APOE with disease course and severity stratified by gender in 221 patients with multiple sclerosis from two overlapping population-based prevalence cohorts. Women carriers of the E4*epsilon2 allele took longer to attain an Expanded Disability Status Scale score of 6 (p = 0.015) and had more favorable ranked severity scores than noncarriers (p = 0.009). There was no association in men. Alleles epsilon3 or epsilon4 and promoter polymorphisms were not associated with disease course or severity.


Assuntos
Apolipoproteínas E/genética , Esclerose Múltipla/genética , Adulto , Apolipoproteína E4 , Feminino , Humanos , Masculino , Esclerose Múltipla/fisiopatologia , Polimorfismo Genético , Regiões Promotoras Genéticas , Índice de Gravidade de Doença , Fatores Sexuais
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