RESUMO
A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT)n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR=0.94 (0.89-0.98)). On the basis of a stronger association of (GT)n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease (OR=1.30 (1.04-1.64)) and rheumatoid arthritis (OR=1.60 (1.20-2.13)) and between the -237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR=0.60 (0.43-0.84)). Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.
Assuntos
Doenças Autoimunes/genética , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença , Infecções/genética , Polimorfismo Genético , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Doenças Autoimunes/epidemiologia , Humanos , Infecções/epidemiologia , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasAssuntos
Neoplasias Colorretais/genética , Estrona/genética , Sequência de Bases , Metilação de DNA , Análise Mutacional de DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites/genética , Mutação , Mutação de Sentido Incorreto , Regiões Promotoras Genéticas/genéticaRESUMO
C17orf1, a gene expressed in skeletal muscle and heart, was initially isolated from a fetal brain cDNA library and localized centromeric to and partially within the proximal CMT1A-REP element. A second gene, COX10, spans the distal CMT1A-REP element, and a duplicated exon of this gene is present in the proximal CMT1A-REP element. C17orf1 includes this duplicated COX10 exon within its sequence; however, the DNA strand opposite to that of the COX10 gene is utilized. We have determined the genomic organization of C17orf1 and found it to be oriented in the direction opposite to COX10. Analysis of the genomic structure of C17orf1 has revealed that it contains at least six exons and spans a length of at least 17 kb. All but one of the splice sites conform to the GT/AG rule, and in this case the splice acceptor site within intron 1 is GA instead of the expected AG. Sequencing and mapping analyses have shown that the centromeric boundary of the proximal CMT1A-REP element lies within intron 5. A 7-bp insertion, identified from genomic sequencing of cosmid clones and verified in the original cDNA clone and RT-PCR products, has extended the previously reported open reading frame from 591 to 756 bp. C17orf1 therefore encodes a 252-amino-acid protein.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteínas/genética , Alquil e Aril Transferases/genética , Mapeamento Cromossômico , Clonagem Molecular , Complexo IV da Cadeia de Transporte de Elétrons , Duplicação Gênica , Humanos , Proteínas de Membrana/genética , Dados de Sequência Molecular , Mapeamento Físico do Cromossomo , Splicing de RNA/genética , Sequências Repetitivas de Ácido Nucleico/genética , Análise de Sequência de DNARESUMO
Misalignment between the two elements of the CMT1A-REP binary repeat on chromosome 17p11.2-p12 causes two inherited peripheral neuropathies, Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies. This binary repeat contains repetitive DNA elements that include LINES, SINES, medium reiteration frequency repeats, and a transposon-like element. The COX10 gene has been mapped 10 kb centromeric to the distal CMT1A-REP element, and a portion of this gene is present in both the proximal and the distal CMT1A-REP elements. We report the isolation and characterization of a novel cDNA (C170RF1), which maps centromeric to and partially within the proximal CMT1A-REP element. Part of C170RF1 is transcribed from the opposite strand of the COX10 partial gene duplication present in the proximal CMT1A-REP element. This finding shows that C170RF1 and COX10 are being transcribed from opposite strands of identical DNA sequences that are separated by 1.5 Mb in the genome. RT-PCR analysis showed the proximal transcript was expressed in skeletal muscle. Sequence analysis identified an open reading frame encoding a 199-amino-acid protein. Zoo blot analysis showed that the transcript is conserved in nonhuman primates. The presence of a binary repeat contributes to the instability of this region of chromosome 17, yet two CMT1A-REP elements are present in the chimpanzee and all human populations. The presence of expressed sequences in both elements of the CMT1A-REP binary repeat could explain the maintenance of this repeat in humans.
Assuntos
Alquil e Aril Transferases/genética , Doença de Charcot-Marie-Tooth/genética , Homologia de Genes/genética , Proteínas de Membrana/genética , Família Multigênica/genética , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , Complexo IV da Cadeia de Transporte de Elétrons , Genes/genética , Humanos , Dados de Sequência Molecular , Músculo Esquelético/química , Miocárdio/química , Especificidade de Órgãos , Primatas , RNA Mensageiro/análise , Sequências Repetitivas de Ácido Nucleico/genética , Alinhamento de Sequência , Análise de Sequência de DNA , Especificidade da Espécie , Transcrição GênicaRESUMO
DNA mapping studies in two families provide further information on the Angelman syndrome critical region, which has recently been defined by the gene UBE3A. The first family has probable familial Angelman syndrome with a maternally imprinted inheritance pattern. A 5 year old girl with this disorder has a 14 year old brother and an 11 year old male cousin who have less typical clinical features. DNA microsatellite analysis has shown that the three share a common segment of the same grandpaternal chromosome 15q11-q13 that overlaps with UBE3A. The child with typical Angelman syndrome has an additional maternal recombination 5' to UBE3A. The second family is a mother and son both of whom have mental retardation but no other features of Angelman syndrome despite an extensive DNA deletion on the telomeric side of UBE3A. Together, the two families identify a region between loci D15S210 and D15S986 which forms part of the Angelman syndrome critical region. A new microsatellite (D15S1234) is described which can be used in place of the LS6-1 marker at locus D15S113.
Assuntos
Síndrome de Angelman/genética , Adolescente , Centrômero , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 15 , Deficiências do Desenvolvimento/genética , Face/anormalidades , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Recombinação Genética , TelômeroRESUMO
Synthetic oligonucleotide primers based on cDNA sequence were used to amplify the region spanning intron 2 of the alpha-globin gene of the bivalve mollusc Anadara trapezia. Amplification of this region from individual clams showed highly polymorphic patterns. The sequence of this intron was found to include a number of mono- [d(T)n and d(C)n], di- [d(CA)n and d(CT)n] and tetranucleotide d(CTGT)n repeats which were found to be polymorphic with respect to the types and numbers of repeats present. Two separate repeat-containing polymorphic regions were located near each end of this intron. The repeat at the 3' end consisted of an unusual example of a d(T)n polymorphism at the position of the polypyrimidine tract usually involved in intron splicing. Thirteen individual cloned intron 2 sequences, derived by PCR amplification from pooled genomic DNA, were sequenced without finding two identical sequences. All of the sequenced clones contained microsatellite sequences.
Assuntos
Bivalves/genética , Globinas/genética , Íntrons/genética , Repetições de Microssatélites/genética , Animais , Sequência de Bases , Clonagem Molecular , Genes/genética , Dados de Sequência Molecular , Polimorfismo Genético , Análise de Sequência de DNARESUMO
Angelman syndrome (AS) is caused by the loss of function of undefined gene(s) on human chromosome 15. The majority of subjects have deletions involving maternally-derived chromosome 15q11-q13, and the shortest region of deletion overlap (SRO) has been localized to the region between D15S10 and D15S113. In this study, yeast artificial chromosomes (YACs), 6G-D4, 9H-D2 and 37D-F9, mapping within the AS SRO, were isolated from the ICI YAC library. Alu-vector PCR products were amplified from the YACs and from YACs A229A2 and A33F10 which had been obtained from the St. Louis YAC library. The PCR products were cloned and sequenced, and three new sequence-tagged sites were generated within the AS SRO, facilitating the characterization of gene(s) involved in the Angelman syndrome.
Assuntos
Síndrome de Angelman/genética , Cromossomos Humanos Par 15/genética , Sitios de Sequências Rotuladas , Sequência de Bases , Cromossomos Artificiais de Levedura , Clonagem Molecular , Primers do DNA/genética , Marcadores Genéticos , Vetores Genéticos , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido NucleicoRESUMO
Three pairs of oligonucleotide primers based on partial DNA and amino acid sequences were used in a combination of PCR experiments to amplify the beta-globin gene of the bivalve mollusc Anadara trapezia. The sequence of 2,139 bp presented contains the whole of the beta-globin gene with the exception of the 5' flanking sequence. This gene possesses the three-exon-and-two-intron gene structure typical of vertebrate globin genes but the lengths of the introns (762 bp and 690 bp, respectively) are only approximately half the size of those present in a beta-variant gene previously characterized from this organism. The encoded amino acid sequence shows two changes when compared to the previously published amino acid sequence.
Assuntos
Evolução Biológica , Globinas/genética , Invertebrados/genética , Moluscos/genética , Vertebrados/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA/análise , Primers do DNA , Éxons , Variação Genética , Íntrons , Dados de Sequência Molecular , Reação em Cadeia da Polimerase/métodos , Mapeamento por RestriçãoRESUMO
1. PCR was carried out on cDNA which had been synthesized from poly(A)+ RNA extracted from A. trapezia red blood cells. 2. A 348 bp product encoding the C-terminal region of the alpha-globin chain and another product encoding a portion of the beta-globin chain were isolated. 3. The C-terminal alpha-chain sequence, encoded by the cDNA, differs from the previously published sequence and these changes improve the alignment of this chain with the other globin chains of this organism.