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1.
Brain ; 146(3): 968-976, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181424

RESUMO

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.


Assuntos
Síndrome do Cabeceio , Oncocercose , Estados Unidos , Humanos , Estudos de Coortes , Imunomodulação , Genômica
2.
AJNR Am J Neuroradiol ; 42(9): 1566-1575, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34326105

RESUMO

Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant information to guidelines currently based on the quantification of stenosis.


Assuntos
Doenças das Artérias Carótidas , Estenose das Carótidas , Placa Aterosclerótica , Acidente Vascular Cerebral , Artérias Carótidas , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/terapia , Consenso , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/prevenção & controle
3.
J Womens Health (Larchmt) ; 30(2): 265-269, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33227226

RESUMO

The pregnancy-related mortality rate in the US exceeds that of other developed nations and is marked by significant disparities in outcome by race. This article reviews the evidence supporting the implementation of a variety of best practices designed to reduce maternal mortality. Evidence from maternal mortality review committees suggests that delays in diagnosis, delays in initiation of treatment and use of ineffective treatments contribute to preventable cases of maternal death. We review several protocols for maternal warning signs that have been used successfully to facilitate early identification and intervention. Care bundles, a collection of best practices, have been developed and implemented to address several maternal emergencies. We review the evidence that supports reduction in adverse outcomes with consistent implementation of obstetric hemorrhage and severe hypertension bundles in a collaborative, team-based setting. The article concludes with suggestions for the future.


Assuntos
Morte Materna , Mortalidade Materna , Feminino , Hemorragia , Humanos , Gravidez , Medição de Risco
5.
Oncogene ; 35(47): 6077-6086, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27157619

RESUMO

Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that 2 of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, 2 of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch3/antagonistas & inibidores , Receptor Notch3/genética , Substituição de Aminoácidos , Animais , Linhagem Celular Tumoral , Códon , Modelos Animais de Doenças , Epitopos/química , Epitopos/imunologia , Feminino , Humanos , Camundongos , Modelos Moleculares , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Conformação Proteica , Receptor Notch3/química , Receptor Notch3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Clin Gastroenterol Hepatol ; 14(6): 896-902, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26820399

RESUMO

BACKGROUND & AIMS: Hepatitis E (HEV) can cause acute-on-chronic liver failure in persons with pre-existing liver disease. We investigated whether HEV infection contributes to hepatic decompensation in patients with previously stable, advanced chronic hepatitis C. METHODS: We performed a case-control study using stored serum samples from subjects enrolled in the randomized phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (n = 1050; mean age, 51 y; 70% male; 40% with cirrhosis at baseline). Cases were subjects who developed hepatic decompensation within a 24-week period. Controls (3 per case) were subjects without hepatic decompensation matched for fibrosis stage and followed up for a similar period. A serum sample obtained within 6 months after the decompensation event in cases and the same follow-up period in controls were tested for anti-HEV IgG. Subjects with a positive result had a baseline sample similarly tested for anti-HEV IgG. We measured levels of anti-HEV IgM and HEV RNA in blood samples from incident cases. RESULTS: Of the 1050 subjects analyzed, 314 (30%) experienced a clinical event. Of the 314 subjects who experienced decompensation as defined, 89 (28%) were tested for anti-HEV, along with 267 controls (without decompensation). Similar proportions of cases and controls tested positive for anti-HEV (22.5% and 20.6%, respectively; P = .70). Ten incident HEV infections were identified-4 in cases (4.5%) and 6 in controls (2.2%) (P = .28). HEV RNA was not detected in blood samples from the 10 incident infections. Only 2 of the 4 incident infections among cases were related temporally to the decompensation event. CONCLUSIONS: HEV does not appear to be a significant cause of hepatic decompensation among persons with previously stable, advanced chronic hepatitis C in the United States.


Assuntos
Insuficiência Hepática Crônica Agudizada/epidemiologia , Hepatite C Crônica/complicações , Hepatite E/complicações , Adulto , Estudos de Casos e Controles , Feminino , Anticorpos Anti-Hepatite/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos
7.
Opt Express ; 18(14): 15267-82, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20640013

RESUMO

The drug development industry is faced with increasing costs and decreasing success rates. New ways to understand biology as well as the increasing interest in personalized treatments for smaller patient segments requires new capabilities for the rapid assessment of treatment responses. Deployment of qualified imaging biomarkers lags apparent technology capabilities. The lack of consensus methods and qualification evidence needed for large-scale multi-center trials, as well as the standardization that allows them, are widely acknowledged to be the limiting factors. The current fragmentation in imaging vendor offerings, coupled with the independent activities of individual biopharmaceutical companies and their contract research organizations (CROs), may stand in the way of the greater opportunity were these efforts to be drawn together. A preliminary report, "Volumetric CT: a potential biomarker of response," of the Quantitative Imaging Biomarkers Alliance (QIBA) activity was presented at the Medical Imaging Continuum: Path Forward for Advancing the Uses of Medical Imaging in the Development of New Biopharmaceutical Products meeting of the Extended Pharmaceutical Research and Manufacturers of America (PhRMA) Imaging Group sponsored by the Drug Information Agency (DIA) in October 2008. The clinical context in Lung Cancer and a methodology for approaching the qualification of volumetric CT as a biomarker has since been reported [Acad. Radiol. 17, 100-106, 107-115 (2010)]. This report reviews the effort to collect and utilize publicly available data sets to provide a transparent environment in which to pursue the qualification activities in such a way as to allow independent peer review and verification of results. This article focuses specifically on our role as stewards of image sets for developing new tools.


Assuntos
Biomarcadores Tumorais/metabolismo , Tomografia Computadorizada de Feixe Cônico/métodos , Bases de Dados como Assunto , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Ensaios Clínicos como Assunto , Humanos , Estadiamento de Neoplasias , Imagens de Fantasmas , Fatores de Tempo
8.
Ann Oncol ; 21(9): 1751-1755, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20332135

RESUMO

SPECIFIC AIM: To review the evidence indicating that volumetric image analysis of computed tomography scans meets specifications for qualification as a biomarker in clinical trials or the management of individual patients with lung cancer. METHODS: Claims of value were broken down into questions about technical feasibility, accuracy, the precision of measurement, sensitivity, the correlations with health outcomes, and the risks of producing misleading information. For each claim, the pertinent literature was reviewed. RESULTS: Technical feasibility has now been shown, but only in limited contexts. Accuracy has been demonstrated, but only for tumors with favorable anatomical features. Measurement error still makes the assessment of change in small nodules precarious in diagnostic settings unless rigorous image acquisition and analysis procedures are followed. Precision is sufficient in some larger masses to make volumetrics a sensitive biomarker. In a few trials, correlations with clinical outcomes have been higher for volumetric-based measures than for unidimensional or bidimensional diameters. Value in clinical practice settings and clinical trials has been suggested, but not proven. CONCLUSION: The weight of the evidence indicates there are circumstances in which volumetric image analysis adds value to clinical trial science and the practice of medicine.


Assuntos
Biomarcadores Tumorais , Neoplasias Pulmonares/patologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/terapia , Prognóstico
9.
J Biol Chem ; 276(23): 20397-406, 2001 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-11259407

RESUMO

Exon trapping and cDNA selection procedures were used to search for novel genes at human chromosome 11p13, a region previously associated with loss of heterozygosity in epithelial carcinomas. Using these approaches, we found the ESE-2 and ESE-3 genes, coding for ETS domain-containing transcription factors. These genes lie in close proximity to the catalase gene within a approximately 200-kilobase genomic interval. ESE-3 mRNA is widely expressed in human tissues with high epithelial content, and immunohistochemical analysis with a newly generated monoclonal antibody revealed that ESE-3 is a nuclear protein expressed exclusively in differentiated epithelial cells and that it is absent in the epithelial carcinomas tested. In transient transfections, ESE-3 behaves as a repressor of the Ras- or phorbol ester-induced transcriptional activation of a subset of promoters that contain ETS and AP-1 binding sites. ESE-3-mediated repression is sequence- and context-dependent and depends both on the presence of high affinity ESE-3 binding sites in combination with AP-1 cis-elements and the arrangement of these sites within a given promoter. We propose that ESE-3 might be an important determinant in the control of epithelial differentiation, as a modulator of the nuclear response to mitogen-activated protein kinase signaling cascades.


Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Bases , Cromossomos Humanos Par 11 , Clonagem Molecular , DNA , Epitélio/metabolismo , Humanos , Imuno-Histoquímica , Dados de Sequência Molecular , Filogenia , Proteínas Repressoras/genética , Homologia de Sequência do Ácido Nucleico , Fatores de Transcrição/genética
10.
Hepatology ; 32(6): 1329-36, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11093740

RESUMO

The molecular basis of Wilson disease (WD), an autosomal recessive disorder, is the presence of mutations in the ATP7B gene, a copper transporting ATPase. Hospital records indicated a higher prevalence of WD (1 in 2,600) in some counties in the northeastern region of the island of Gran Canaria (Canary Islands, Spain) that was around 10-fold higher than that described for European populations (1 in 30,000). The ATP7B gene was analyzed for mutations in 24 affected subjects, revealing a high prevalence of the rare Leu708Pro mutation present in 12 homozygous and 7 heterozygous individuals. In these patients, who constitute one of the largest described cohorts of WD homozygotes, we found a variable clinical presentation of the disease, although the biochemical picture was homogenous and characteristic, thereby confirming that the Leu708Pro change is indeed a mutation associated with WD. Haplotype analysis of subjects homozygous for the Leu708Pro mutation showed a conserved shared region smaller than 1 centimorgan (cM), and the region of linkage disequilibrium between the Leu708Pro mutation and neighboring microsatellite markers extended approximately 4.6 cM. When comparing the amount of linkage disequilibrium versus genetic distance from the disease mutation, it was estimated that a common ancestral Leu708Pro chromosome may have been introduced in Gran Canaria over 56 generations ago, dating it back to pre-Hispanic times. The prevalence, and the tight geographical distribution of the Leu708Pro chromosome suggests that the Canary Islands can be considered a genetic isolate for linkage disequilibrium studies.


Assuntos
Proteínas de Transporte de Cátions , Degeneração Hepatolenticular/genética , Mutação/genética , Adenosina Trifosfatases/genética , Proteínas de Transporte/genética , Cromossomos/genética , Estudos de Coortes , ATPases Transportadoras de Cobre , Demografia , Frequência do Gene , Ligação Genética , Haplótipos , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Hepatopatias/etiologia , Doenças do Sistema Nervoso/genética , Espanha
11.
Pharmacogenetics ; 10(3): 251-60, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10803681

RESUMO

The UDP-glucuronosyltransferases (UGTs) comprise a large family of proteins capable of detoxifying a wide variety of both endogenous and exogenous substrates. The primary function of this gene superfamily is to catalyze the glycosylation of substrates such as biogenic amines, steroids, bile acids, phenolic compounds and various other pharmacologically relevant compounds, including numerous carcinogens, toxic environmental pollutants and prescription drugs. This conjugation increases the solubility of these compounds, allowing them to be excreted more readily through hepatic or renal mechanisms. This paper describes the genomic characterization and chromosomal localization of three UGT2B genes which together comprise part of a large cluster of related sequences, including pseudogenes found on human chromosome 4q13. A genomic map spanning approximately 500-1000 kb of this region reveals the presence of three previously described UGT2B genes, at least two previously uncharacterized pseudogenes and a significant number of remnant gene fragments and places UGT2B4 between UGT2B7 and UGT2B15. Additionally, access to a large reference DNA bank allowed us to calculate allele frequencies for two UGT2B SNPs: D85R in UGT2B15 and Q458D in UGT2B4 amongst 803 unrelated individuals representing five ethnic populations. The data presented here suggest a recent evolutionary history of gene duplication, mutation and rearrangement. Furthermore, they suggest that a re-evaluation of the current description of the UGT2B gene family with respect to the number of specific genes, degree of allelic diversity and molecular evolution may be necessary.


Assuntos
Cromossomos Humanos Par 4/genética , Glucuronosiltransferase/genética , Família Multigênica , Evolução Biológica , Mapeamento Cromossômico , Etnicidade/genética , Frequência do Gene , Biblioteca Genômica , Humanos , Hibridização in Situ Fluorescente , Isoenzimas/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Pseudogenes
12.
Cancer Genet Cytogenet ; 115(1): 56-61, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10565301

RESUMO

A balanced translocation between chromosomes 12 and 14 is commonly seen in uterine leiomyoma (UL). We have previously cloned and characterized a 2 Mb segment of human chromosomal subband 14q24.1, and have shown that the t(12;14)(q15;q24.1) breakpoints from several ULs map within this region. Exon trapping of DNA clones spanning one such breakpoint revealed coding sequences from hREC2, a gene that shows significant amino acid sequence identity to the double-strand break repair enzyme RAD51. We report here that this breakpoint is located within a 19 kb intron of the hREC2 gene and that the translocation results in the premature truncation of the major hREC2 transcript. Mapping and sequence analyses show that alternative transcripts of the hREC2 gene, including novel isoforms identified in testis and uterus, are not interrupted by the translocation.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 14 , Proteínas de Ligação a DNA/genética , Leiomioma/genética , Proteínas/genética , Translocação Genética , Neoplasias Uterinas/genética , Regiões 3' não Traduzidas/genética , Sequência de Aminoácidos , Sequência de Bases , Éxons , Feminino , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Mapeamento Físico do Cromossomo , Isoformas de Proteínas , Rad51 Recombinase , Homologia de Sequência de Aminoácidos
14.
Am J Hum Genet ; 64(3): 808-16, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10053016

RESUMO

Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis-factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes.


Assuntos
Doenças Inflamatórias Intestinais/genética , Estudos de Coortes , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Escore Lod , Masculino
15.
Proc Natl Acad Sci U S A ; 95(23): 13765-70, 1998 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-9811875

RESUMO

X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.


Assuntos
Transtornos Linfoproliferativos/genética , Mutação , Cromossomo X , Domínios de Homologia de src/genética , Sequência de Aminoácidos , Mapeamento Cromossômico , Ligação Genética , Marcadores Genéticos , Humanos , Dados de Sequência Molecular
16.
Gene ; 218(1-2): 17-25, 1998 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-9751798

RESUMO

The mammalian rasGAPs constitute a group of widely expressed proteins involved in the negative regulation of ras-mediated signaling. In this study we have isolated a novel human gene, RASAL (Ras GTPase-activating-like) and its murine ortholog, MRASAL which are most similar to the GAP1 family of rasGAP proteins, based upon the presence and organization of specific conserved domains. Full-length human and murine mRNA sequences are predicted to encode 804 and 799 amino acid polypeptides, respectively. Sequence analysis of these two proteins revealed the presence of two N-terminal calcium-dependent phospholipid binding C2 domains, a conserved GAP related domain (GRD) and a C-terminal pleckstrin homology (PH) domain. Northern blot and mRNA in situ hybridization analyses indicate that RASAL, in contrast to other mammalian rasGAP proteins, has a limited expression pattern; RASAL is highly expressed in the follicular cells of the thyroid and the adrenal medulla and expressed at lower levels in brain, spinal cord and trachea. Human RASAL has been localized by radiation hybrid mapping to chromosome 12q23-24.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas/genética , Proteínas ras/genética , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Clonagem Molecular , GTP Fosfo-Hidrolases/biossíntese , Proteínas Ativadoras de GTPase , Humanos , Camundongos , Dados de Sequência Molecular , Biossíntese de Proteínas , RNA Mensageiro/genética , Alinhamento de Sequência , Proteínas Ativadoras de ras GTPase , Proteínas ras/biossíntese
17.
Genomics ; 52(1): 17-26, 1998 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-9740667

RESUMO

A translocation involving chromosomes 12 and 14 [t(12;14)(q15;24.1)] is commonly seen in benign smooth muscle tumor as uterine leiomyoma (UL). A contig of P1-derived artificial chromosome and bacterial artificial chromosome clones on chromosome 14, encompassing a t(12;14) breakpoint cluster region (BCR) in UL, was generated principally using the recently developed HAPPY map of chromosome 14 as a framework (P. H. Dear et al., 1998, Genomics 48: 232-241). Three UL t(12;14) breakpoints have been localized within this contig, showing that a BCR of at least 400 kb exists on chromosome 14. Other studies of tumors with t(12;14) rearrangements similarly show breakpoints within a 475-kb multiple aberration region on chromosome 12. Thus t(12;14) is an example of a translocation in which the breakpoints are located within a BCR on both chromosome 12 and chromosome 14, justifying the identification of expressed sequences that are altered in these BCR regions. A total of four expressed sequences were identified in the BCR on chromosome 14. Two of these were novel cDNAs (D14S1460E and D14S1461E). The chromosome 14 cDNAs were expressed in multiple adult tissues. The identification of a large breakpoint cluster region on chromosome 14 suggests that translocations in this region mediate their effects at a distance and also that elements that predispose this region to recurrent chromosomal translocation may be widely distributed.


Assuntos
Quebra Cromossômica/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 14/genética , Leiomioma/genética , Translocação Genética/genética , Neoplasias Uterinas/genética , Sequência de Aminoácidos , Sequência de Bases , Southern Blotting , Clonagem Molecular , Feminino , Humanos , Dados de Sequência Molecular , Família Multigênica
19.
Nat Genet ; 17(1): 40-8, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9288096

RESUMO

Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.


Assuntos
Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Chaperonas Moleculares , Transportadores de Cassetes de Ligação de ATP/genética , Idade de Início , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Transporte/química , Mapeamento Cromossômico , Análise Mutacional de DNA , Triagem de Portadores Genéticos , Ligação Genética , Marcadores Genéticos , Humanos , Judeus/genética , Linfócitos , Camundongos , Dados de Sequência Molecular , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Ratos , Proteínas Recombinantes/biossíntese , Alinhamento de Sequência , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Transcrição Gênica
20.
Genome Res ; 7(5): 483-94, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9149944

RESUMO

The DYT1 gene, which maps to chromosome 9q34, appears to be responsible for most cases of early-onset torsion dystonia in both Ashkenazic Jewish (AJ) and non-Jewish families. This disease is inherited in an autosomal dominant mode with reduced penetrance (30%-40%). The abnormal involuntary movements associated with this disease are believed to be caused by unbalanced neural transmission in the basal ganglia. Previous linkage disequilibrium studies in the AJ population placed the DYT1 gene in a 2-cM region between the loci D9S62a and ASS. A YAC contig has now been created spanning 600 kb of this region including D9S62a. The location of the DYT1 gene has been refined within this contig using several new polymorphic loci to expand the linkage disequilibrium analysis of the AJ founder mutation. The most likely location of the DYT1 gene is within a 150 kb region between the loci D9S2161 and D9S63.


Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Judeus/genética , Desequilíbrio de Ligação , Adulto , Cromossomos Artificiais de Levedura , Cosmídeos/genética , Eletroforese em Gel de Campo Pulsado , Marcadores Genéticos , Haplótipos , Humanos , Linhagem , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico
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