RESUMO
A systematic haplotype and sequencing analysis of the HLA-DR and -DQ region in patients with narcolepsy was performed. Five new (CA)n microsatellite markers were generated and positioned on the physical map across the HLA-DQB1-DQA1-DRB1 interval. Haplotypes for these new markers and the three HLA loci were established using somatic cell hybrids generated from patients. A four-marker haplotype surrounding the DQB1(*)0602 gene was found in all narcolepsy patients, and was identical to haplotypes observed on random chromosomes harboring the DQB1(*)0602 allele. Eighty-six kilobases of contiguous genomic sequence across the region did not reveal new genes, and analysis of this sequence for single nucleotide polymorphisms did not reveal sequence variation among DQB1(*)0602 chromosomes. These results are consistent with other studies, suggesting that the HLA-DQ genes themselves are among the predisposing factors in narcolepsy.
Assuntos
Antígenos HLA-DQ/genética , Haplótipos , Narcolepsia/genética , Causalidade , Mapeamento Cromossômico , Marcadores Genéticos , Biblioteca Genômica , Genótipo , Cadeias beta de HLA-DQ , Teste de Histocompatibilidade , Humanos , Repetições de Microssatélites , Narcolepsia/etiologia , Polimorfismo Genético , Análise de Sequência de DNARESUMO
Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.
Assuntos
Antígenos HLA/genética , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Alelos , Sequência de Aminoácidos , Sequência de Bases , Evolução Biológica , Cromossomos Artificiais de Levedura , Cromossomos Humanos Par 6 , Clonagem Molecular/métodos , Cisteína , Primers do DNA/química , Expressão Gênica , Genes MHC Classe I , Marcadores Genéticos , Haplótipos , Proteína da Hemocromatose , Humanos , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade , Dados de Sequência Molecular , RNA Mensageiro/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
The plasma cholesteryl ester transfer protein (CETP) catalyzes the transfer of phospholipids and neutral lipids between the lipoproteins. Thus, this protein may be important in modulating lipoprotein levels in the plasma. We have determined the primary structure and organization of the human CETP gene. Southern blotting of cellular DNA indicated a single copy of the CETP gene exists per haploid genome. Analysis of three overlapping genomic clones showed that the gene spans approximately 25 kbp and contains 16 exons (size range 32-250 bp). Overall, the sequence and organization of the CETP gene do not resemble those of other lipid-metabolizing enzymes or apolipoproteins. However, comparison of the CETP sequence, one exon at a time, with the sequences in the sequence databases revealed a striking identity of a pentapeptide sequence (ValLeuThrLeuAla) within the hydrophobic core of the signal sequences of human CETP, apolipoproteins A-IV and A-I, and lipoprotein lipase. This pentapeptide sequence was not found in the signal sequences of other proteins, suggesting that it may mediate a specialized function related to lipid metabolism or transport.
Assuntos
Apolipoproteínas/genética , Proteínas de Transporte/genética , Ésteres do Colesterol , Genes , Glicoproteínas , Sequência de Aminoácidos , Sequência de Bases , Southern Blotting , Proteínas de Transferência de Ésteres de Colesterol , DNA/genética , Éxons , Haploidia , Humanos , Lipase Lipoproteica/genética , Dados de Sequência Molecular , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Mapeamento por Restrição , Homologia de Sequência do Ácido NucleicoRESUMO
Coronary heart disease risk correlates directly with plasma concentrations of lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle distinguished by the presence of the glycoprotein apolipoprotein(a) (apo(a)), which is bound to apolipoprotein B-100 (apoB-100) by disulfide bridges. Size isoforms of apo(a) are inherited as Mendelian codominant traits and are associated with variations in the plasma concentration of lipoprotein(a). Plasminogen and apo(a) show striking protein sequence homology, and their genes both map to chromosome 6q26-27. In a large family with early coronary heart disease and high plasma concentrations of Lp(a), we found tight linkage between apo(a) size isoforms and a DNA polymorphism in the plasminogen gene; plasma concentrations of Lp(a) also appeared to be related to genetic variation at the apo(a) locus. We found free recombination between the same phenotype and alleles of the apoB DNA polymorphism. This suggests that apo(a) size isoforms and plasma lipoprotein(a) concentrations are each determined by genetic variation at the apo(a) locus.
Assuntos
Genes , Ligação Genética , Lipoproteínas/genética , Plasminogênio/genética , Polimorfismo Genético , Adulto , Feminino , Humanos , Lipoproteína(a) , Masculino , Infarto do Miocárdio/genética , Linhagem , FenótipoRESUMO
The exons and bordering intron nucleotides of the human apolipoprotein D (apo D) gene have been sequenced. The protein-coding portion of the gene is divided into five exons which span approximately 12,000 bp. At least one intron interrupts the 5' untranslated region. The gene has been localized to the p14.2----qter region of human chromosome 3. Apo D shares homology with the alpha 2u-globulin superfamily of genes, including approximately 25% amino acid homology with human retinol-binding protein (RBP). Similarity of intron locations in both apo D and RBP suggests that these two genes derived from a common ancestor.
