RESUMEN
The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Predisposición Genética a la Enfermedad , Lepromina/inmunología , Lepra/inmunología , Proteínas de la Membrana/genética , Piel/inmunología , China/etnología , Femenino , Ligamiento Genético , Granuloma , Haplotipos , Humanos , Inmunidad Innata , Inyecciones Intradérmicas , Lepra Lepromatosa/inmunología , Lepra Tuberculoide/inmunología , Masculino , Núcleo Familiar , Linaje , Fenotipo , Linfocitos T Colaboradores-Inductores , VietnamRESUMEN
The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.
Asunto(s)
Masculino , Femenino , Humanos , Lepromina/inmunología , China/etnología , Granuloma , Lepra Tuberculoide/inmunología , Lepra Lepromatosa/inmunología , Lepra/inmunología , Piel/inmunología , Vietnam , Fenotipo , Haplotipos , Inmunidad Innata , Inyecciones Intradérmicas , Linfocitos T Colaboradores-Inductores , Linaje , Núcleo FamiliarRESUMEN
The human NRAMP1 gene located on Chromosome (Chr) region 2q35 is a candidate gene for increased risk of infection by several intracellular macrophage parasites, including M. tuberculosis and M. leprae. In search for a possible mutational hot spot, we have analyzed a 3.5-kb region 5' to NRAMP1 that is highly enriched for DNA repeat sequences. The repeat sequences could be grouped into one Mer element and six Alu elements, representing five Alu subfamilies, that had integrated in the same DNA region during successive rounds of Alu retropositional activity. Comparative sequence analysis of the Alu cluster region in humans, chimpanzee (Pan paniscus), and gorilla (Gorilla gorilla) revealed only modest sequence variability and failed to detect any evidence for genomic instability of the highly repetitive DNA region. These results show that sequence length variants in the Alu-flanking regions as well as nucleotide substitutions are the most common genomic variations even in a region of extreme Alu-clustering. Moreover, the high degree of sequence conservation among three primate species argues against the Alu cluster being the site of frequent genomic rearrangements or other frequent genetic events that might influence NRAMP1 expression.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Cromosomas Humanos Par 2 , Proteínas de la Membrana/genética , Secuencias Repetitivas de Ácidos Nucleicos , Animales , Secuencia de Bases , Gorilla gorilla , Humanos , Inmunidad Innata/genética , Datos de Secuencia Molecular , Pan paniscus , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
Leprosy is a debilitating infectious disease of human skin and nerves. Genetic factors of the host play an important role in the manifestation of disease susceptibility. The human NRAMP1 gene is a leprosy susceptibility candidate locus since its murine homologue Nramp1 (formerly Lsh/Ity/Bcg) controls innate resistance to Mycobacterium lepraemurium. In this study, 168 members of 20 multiplex leprosy families were genotyped for NRAMP1 alleles and 4 closely linked polymorphic markers. Highly informative haplotypes overlapping the NRAMP1 gene were constructed, and the haplotype segregation into leprosy-affected offspring was analyzed. It was observed that the segregation of NRAMP1 haplotypes into affected siblings was significantly nonrandom. This finding is consistent with the hypothesis that NRAMP1 itself is a leprosy susceptibility locus.