RESUMEN
It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).
Asunto(s)
Cromosomas Humanos Par 17/genética , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Secuencia de Aminoácidos , Clonación Molecular/métodos , ADN Complementario/genética , Efecto Fundador , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Datos de Secuencia Molecular , Mutación Missense , Linaje , ARN Mensajero/genética , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , UtahRESUMEN
Eosinophils are granulocytic leukocytes that function in both protective and pathological immune responses. They can be infected by HIV-1, but characterization of the infection has been hindered by lack of a productive cell culture model. In the present study, the unique eosinophilic cell line AML14.3D10 was used as a model to test the hypothesis that HIV-1 productively infects eosinophilic cells in a strain-dependent fashion. The AML14.3D10 cell line was cultured with one T cell-tropic (T-tropic) strain and two macrophage-tropic (M-tropic) strains of HIV-1 (HTLV-IIIB, HIV-1AdaM, and HIV-1Ba-L strains, respectively). Cytopathic effects were evident in living cultures and in stained slide preparations of AML14.3D10 cells infected with the T-tropic strain of HIV-1. Culture supernatants from infected AML14.3D10 cells contained high levels of HIV-1 p24 protein that peaked at approximately 7-10 days postinfection. A line of AML14.3D10 cells chronically infected with HTLV-IIIB and continuously producing high levels of virus was established. In contrast to the T-tropic strain, the M-tropic strains of HIV-1 did not productively infect the eosinophilic cell line. Thus, the AML14.3D10 eosinophilic cell line was permissive for a T-tropic strain but not for M-tropic strains of HIV-1. Flow cytometry revealed that uninfected AML14.3D10 cells were positive for the HIV-1 receptor CD4 and coreceptors CXCR4 and CCR5; the cell line was negative for CCR3. The lack of productive infection by M-tropic strains despite CCR5 expression indicates that strain-dependent infection may not be determined at the coreceptor level in AML14.3D10 cells.