RESUMO
Holt-Oram syndrome (HOS) is an autosomal dominant condition affecting the heart and upper limbs. We have sought to identify the location of this gene using microsatellite DNA markers in a linkage study. Of seven families analysed, five show linkage between HOS and markers on chromosome 12q. But the two remaining families, phenotypically indistinguishable from the others, do not show this linkage. Analysis with the computer program HOMOG indicates that HOS is a heterogeneous disease. Our analysis places one HOS locus in a 21 cM interval in the distal region of chromosome 12q. The localization of a gene for HOS, reported here, represents an important step towards a better understanding of limb and cardiac development.
Assuntos
Anormalidades Múltiplas/genética , Braço/anormalidades , Cromossomos Humanos Par 12 , Genes Dominantes , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Anormalidades Múltiplas/classificação , Mapeamento Cromossômico , Troca Genética , DNA Satélite/genética , Feminino , Marcadores Genéticos , Deformidades Congênitas da Mão/classificação , Cardiopatias Congênitas/classificação , Humanos , Masculino , Linhagem , SíndromeRESUMO
Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBX5 gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development.
Assuntos
Anormalidades Múltiplas/genética , Braço/anormalidades , Cardiopatias Congênitas/genética , Proteínas com Domínio T , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Cromossomos Artificiais de Levedura , Cromossomos Humanos Par 12 , DNA , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/metabolismo , Feminino , Proteínas Fetais/genética , Expressão Gênica , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Família Multigênica , Linhagem , RNA Mensageiro/genética , Homologia de Sequência de Aminoácidos , Síndrome , Transcrição Gênica , Translocação GenéticaRESUMO
T-box genes are important development regulators in vertebrates with specific patterns of expression and precise roles during embryogenesis. They encode transcription factors that regulate gene transcription, often in the early stages of development. The hallmark of this family of proteins is the presence of a conserved DNA binding motif, the "T-domain." Mutations in T-box genes can cause developmental disorders in humans, mostly due to functional deficiency of the relevant proteins. Recent studies have also highlighted the role of some T-box genes in cancer and in cardiomyopathy, extending their role in human disease. In this review, we focus on ten T-box genes with a special emphasis on their roles in human disease.
Assuntos
Doença , Desenvolvimento Embrionário/genética , Proteínas com Domínio T/genética , Animais , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Mutação/genética , Proteínas com Domínio T/metabolismoRESUMO
Myotonic dystrophy (DM1) is the most common form of adult muscular dystrophy and is inherited as an autosomal dominant trait. The genetic basis of DM1 is the expansion of a CTG repeat in the 3' untranslated region of a protein kinase gene (DMPK). The molecular mechanism by which this expanded repeat produces the pathophysiology of DM1 remains unknown. Transcripts from the expanded allele accumulate as foci in the nucleus of DM1 cells and it has been suggested that these transcript foci sequester cellular proteins that are required for normal nuclear function. We have investigated the role of three RNA-binding proteins, CUG-BP, hnRNP C and MBNL, as possible sequestered factors. Using a combination of indirect immunofluorescence to detect endogenous proteins and overexpression of proteins with green fluorescent protein (GFP) tags we have shown that CUG-BP and hnRNP C do not co-localise with expanded repeat foci in DM1 cell lines. However, GFP-tagged MBNL does itself form foci in DM1 cell lines and co-localises with the foci of expanded repeat transcripts. GFP-tagged MBNL does not appear as foci in non-DM1 cell lines. This work provides further support for the involvement of MBNL in DM1.
Assuntos
Distrofia Miotônica/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a RNA/metabolismo , Expansão das Repetições de Trinucleotídeos/genética , Regiões 3' não Traduzidas/genética , Proteínas CELF1 , Fibroblastos , Técnica Indireta de Fluorescência para Anticorpo , Ribonucleoproteínas Nucleares Heterogêneas Grupo C , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Hibridização In Situ , Microscopia de Fluorescência , Miotonina Proteína Quinase , Ligação Proteica , Transporte Proteico , Proteínas de Ligação a RNA/genética , Proteínas Recombinantes de Fusão/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , TransfecçãoRESUMO
Fifty-four grade 1 tubular breast cancers and nine non-comedo ductal carcinoma in situ samples have been analyzed for loss of heterozygosity using a series of microsatellite markers. Markers mapping to regions of the genome for which loss of heterozygosity has been documented previously in higher-grade breast cancers were selected for this analysis. Even within this group of good prognostic early breast cancers, genetic events are very common. The highest levels of loss were observed for D3S1300, which maps within an intron of the recently identified FHIT gene. High levels of loss were also observed within the ATM gene. These findings indicate that allele loss at FHIT and ATM may be an important early event in the development of sporadic breast cancer.
Assuntos
Hidrolases Anidrido Ácido , Adenocarcinoma/genética , Neoplasias da Mama/genética , Carcinoma in Situ/genética , Carcinoma Ductal de Mama/genética , Deleção de Genes , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases , Proteínas/genética , Adenocarcinoma/patologia , Alelos , Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias da Mama/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/patologia , Proteínas de Ciclo Celular , Transformação Celular Neoplásica/genética , Cromossomos Humanos/genética , DNA de Neoplasias/genética , Proteínas de Ligação a DNA , Feminino , Heterozigoto , Humanos , Repetições de Microssatélites , Invasividade Neoplásica , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Proteínas Supressoras de TumorRESUMO
The effect of 4CMB on meiosis in the mouse was studied using both male and female test systems. Females were superovulated and treated with 4CMB at metaphase I and oocytes sampled at metaphase II. Similarly with males, chromosome analysis was made at metaphase II for spermatocytes treated at metaphase I. No increase in the frequency of structural of numerical chromosome abnormalities was noted for treated mice as compared to controls.
Assuntos
Compostos de Bifenilo/farmacologia , Meiose/efeitos dos fármacos , Mutagênicos/farmacologia , Oócitos/efeitos dos fármacos , Óvulo/efeitos dos fármacos , Espermatócitos/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Gonadotropina Coriônica/farmacologia , Aberrações Cromossômicas , Feminino , Gonadotropinas Equinas/farmacologia , Masculino , Metáfase/efeitos dos fármacos , Camundongos , Testes de Mutagenicidade , Ovulação/efeitos dos fármacosRESUMO
The 3 chemicals, 6 mercaptopurine (6-MCP), phenylalanine and para-fluorophenylalanine (pFPA) have been tested on mouse oocytes of the Swiss strain for possible aneuploidy-inducing effects. Tests were made at the dictyate stage in young and aged females and at the preovulatory (diakinesis/MI) stage in aged females only. Metaphase II chromosome complements were analysed for aneuploidy resulting from segregational errors arising at the first meiotic division. No evidence of non-disjunction was found either in treated or control groups up to the age of 40 weeks tested. The need to select for gametogenic stage and strain when using a mouse model system for aneuploidy testing, is considered.
Assuntos
Aneuploidia , Oócitos/efeitos dos fármacos , Envelhecimento , Animais , Feminino , Meiose/efeitos dos fármacos , Mercaptopurina/toxicidade , Camundongos , Testes de Mutagenicidade , Fenilalanina/toxicidade , p-Fluorfenilalanina/toxicidadeRESUMO
Dyad scores of metaphase II spermatocytes in the mouse have been used as an end point to assess the aneuploidy-inducing potential of three different chemicals; p-fluorophyalanine, phenylalanine and 6-mercaptopurine. The sensitivities of three different spermatogenic stages have been tested; pre-leptotene, zygotene and metaphase I. No effect was found at any treated stage for 6-mercaptopurine and phenylalanine. p-Fluorophenylalanine, when compared to control treatments, did, however, induce non-disjunction when applied at metaphase I. It also caused a delay to spermatogenesis when applied at this stage. The potential of mammalian test systems for the routine screening of chemicals as non-disjunction inducers, is discussed.
Assuntos
Aneuploidia , Meiose/efeitos dos fármacos , Mercaptopurina/farmacologia , Testes de Mutagenicidade/métodos , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Espermatogênese/efeitos dos fármacos , p-Fluorfenilalanina/farmacologia , Animais , Masculino , Metáfase , Camundongos , Espermatócitos/efeitos dos fármacos , Fatores de TempoAssuntos
Cardiopatias Congênitas/genética , Deformidades Congênitas dos Membros/genética , Deleção de Sequência/genética , Proteínas com Domínio T/genética , Análise Mutacional de DNA , Éxons/genética , Feminino , Genes Dominantes/genética , Testes Genéticos , Humanos , Masculino , Linhagem , SíndromeAssuntos
Cromossomos Humanos 19-20 , Distrofia Miotônica/genética , Sequência de Bases , Aberrações Cromossômicas , Mapeamento Cromossômico , Clonagem Molecular , DNA/genética , Enzimas de Restrição do DNA , Regulação da Expressão Gênica , Ligação Genética , Vetores Genéticos , Humanos , Células Híbridas/fisiologia , Distrofia Miotônica/diagnóstico , Hibridização de Ácido Nucleico , Polimorfismo Genético , Diagnóstico Pré-NatalRESUMO
Maternal ageing remains the overwhelming factor in the aetiology of human aneuploidy. Whether aberrant meiotic chromosome segregation in the oocyte relates causally to ovarian physiological ageing or to some factor dependent on the passage of chronological time, remains to be determined. The present experimental studies in the mouse indicate the former. An earlier cessation of reproductive life, brought on by unilateral ovariectomy in CBA females, resulted in the earlier onset of irregular cyclicity and an earlier rise in aneuploidy. The results could not be explained on the basis of the "production line" hypothesis. The clinical implications are that the probability of conceiving a Down foetus will be determined by distance in time from the approaching menopause, rather than by the chronological age of the woman per se.
Assuntos
Envelhecimento , Aneuploidia , Embrião de Mamíferos/ultraestrutura , Idade Materna , Ovário/fisiologia , Animais , Castração , Feminino , Humanos , Camundongos , Camundongos Endogâmicos CBA , GravidezRESUMO
We have used exon amplification to identify putative transcribed sequences from an 823-kb contig consisting of 28 cosmids that form a minimum tiling path from the interval 19p12-p13.1. This region contains the genes responsible for multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). We have trapped 66 exons (an average of 2.4 exons per cosmid) from pools of 2 or 3 cosmids. The majority of exons (51.5%) show only weak similarity or no similarity (36.3%) to sequences in current databases. Six of 8 exons examined from these groups, however, show cross-species sequence conservation, indicating that many of them probably represent authentic exons. Eight exons show identity or significant similarity to ESTs or known genes, including the human TNF receptor 3 '-flanking region gene, human epoxide hydrolase (EPHX), human growth/differentiation factor (GOF-1), human myocyte-specific enhancer factor 2, the rat neurocan gene, and the human cartilage oligomeric matrix protein gene (COMP). Mutations in this latter gene have recently been shown to be responsible for MED and PSACH.
Assuntos
Cromossomos Humanos Par 19 , Éxons , Osteocondrodisplasias/genética , Sequência de Aminoácidos , Animais , Proteoglicanas de Sulfatos de Condroitina/química , Proteoglicanas de Sulfatos de Condroitina/genética , Humanos , Lectinas Tipo C , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurocam , Homologia de Sequência de AminoácidosRESUMO
The eukaryotic translation initiation factor (eIF-4E) has recently been cloned from human, mouse, and yeast. This polypeptide is the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis. We have designed oligonucleotide primers to the 3' untranslated region of the gene encoding eIF-4E and specifically amplified the human gene in human/rodent somatic cell hybrids using the polymerase chain reaction. By this method, one of the human eIF-4E genes (EIF4EL1, eukaryotic translation initiation factor 4E-like 1) has been mapped to human chromosome 4qter-4p15. In addition, we have localized a second eIF-4E gene (EIF4EL2, eukaryotic translation initiation factor 4E-like 2) to human chromosome 20 by Southern blot analysis of mapping panels established from human/rodent somatic cell hybrids.
Assuntos
Cromossomos Humanos Par 20 , Cromossomos Humanos Par 4 , Fatores de Iniciação de Peptídeos/genética , Animais , Sequência de Bases , Linhagem Celular , Clonagem Molecular , DNA/sangue , DNA/genética , Eritrócitos/fisiologia , Fator de Iniciação 4E em Eucariotos , Humanos , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Saccharomyces cerevisiae/genética , Homologia de Sequência do Ácido NucleicoRESUMO
The Tbx2/3/4/5 subfamily is one of the largest subgroupings within the T-box gene family, the members of which encode developmentally critical transcription factors. TBX4, a human member of the Tbx2/3/4/5 subfamily, has been identified and characterized from a high-throughput genomic sequence. The genomic organization of TBX4 was elucidated by computational sequence analysis, and the putative cDNA sequence was assembled. The genomic organization of TBX4 is very similar to that of TBX5, as is the situation for TBX2 and TBX3. The physical configuration of the TBX4-TBX2 cluster on human chromosome 17q21-q22 is similar to that of the TBX5-TBX3 cluster on chromosome 12q23-q24. The assembled TBX4 cDNA sequence was searched against the EST databases, and a TBX4 EST was identified.
Assuntos
Proteínas com Domínio T/genética , Sequência de Bases , Cromossomos Artificiais , Cromossomos Bacterianos , Cromossomos Humanos Par 17 , Clonagem Molecular , Biologia Computacional , Bases de Dados Factuais , Éxons , Etiquetas de Sequências Expressas , Humanos , Íntrons , Dados de Sequência Molecular , Família Multigênica , Mapeamento Físico do CromossomoRESUMO
The human malignant melanoma cell line NK14 contains a novel transforming gene which was identified using DNA transfection into NIH3T3 cells (1). This gene has been assigned to chromosome 19p13.2-q13.2 using human-mouse and human-hamster somatic cell hybrids.
Assuntos
Cromossomos Humanos Par 19 , Oncogenes , Animais , Linhagem Celular , Mapeamento Cromossômico , Cricetinae , Humanos , Células Híbridas/citologia , Melanoma/genética , CamundongosRESUMO
We have isolated a human-specific repetitive sequence with a copy number of several hundred (p11L26). Using Southern blots of EcoR1-digested DNA from somatic cell hybrids containing one or a few human chromosomes, band patterns specific for those chromosomes can be generated by hybridization with p11L26. Genomic copies of the sequence have also been mapped to subchromosomal regions using translocations. The probe offers a useful addition to the standard techniques for mapping human chromosomes in hybrid cell lines.
Assuntos
Mapeamento Cromossômico , Sequências Repetitivas de Ácido Nucleico , Animais , Clonagem Molecular , Cricetinae , Enzimas de Restrição do DNA , Humanos , Células Híbridas , Camundongos , Cromossomo X , Cromossomo YRESUMO
The genes encoding apolipoproteins CI, CII, and E have been previously localized to chromosome 19. By use of rodent-human hybrid cell lines containing translocations of chromosome 19 we have now mapped these three genes to the region 19p13-19q13 and most probably 19p13-19cen. The clustering of APOC1, APOC2, and APOE must reflect their common evolutionary background and suggests that they may be coordinately regulated. Polymorphisms detected for any one gene will be useful for inheritance studies of all three.
Assuntos
Apolipoproteínas C/genética , Apolipoproteínas E/genética , Mapeamento Cromossômico , Cromossomos Humanos 19-20 , Animais , Apolipoproteína C-I , Apolipoproteína C-II , Linhagem Celular , Cricetinae , DNA/genética , Enzimas de Restrição do DNA , Genes , Marcadores Genéticos , Humanos , Células Híbridas , Camundongos , Polimorfismo GenéticoRESUMO
A panel of human-rodent somatic cell hybrids containing translocation derivatives of human chromosome 19 has been used to assign the markers peptidase D, complement component 3, lysosomal mannosidase, lysosomal DNAase, chorionic gonadotropin beta-subunit, and a new polymorphic DNA sequence, to specific regions of chromosome 19. This has allowed the relative orientations of the genetic and physical maps to be established, and provides the framework for a search for the genes responsible for inherited disorders on chromosome 19, such as myotonic dystrophy and neurofibromatosis.