RESUMEN
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients is linked to JC virus (JCV) infection. JCV sequence variation and rearrangements influence viral pathogenicity and tropism. To better understand PML development, we analyzed viral DNA sequences in blood, CSF and/or urine of natalizumab-treated PML patients. METHODS: Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding region, and the entire 5 kb viral genome. RESULTS: Analysis of JCV from multiple biofluids revealed that individuals were infected with a single genotype. Across our patient cohort, multiple PML-associated NCCR rearrangements and VP1 mutations were present in CSF and blood, but absent from urine-derived virus. NCCR rearrangements occurred in CSF of 100% of our cohort. VP1 mutations were observed in blood or CSF in 81% of patients. Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could occur without VP1 mutations, but VP1 mutations were not observed without NCCR rearrangement. CONCLUSIONS: These data confirm that JCV in natalizumab-PML patients is similar to that observed in other PML patient groups, multiple genotypes are associated with PML, individual patients appear to be infected with a single genotype, and PML-associated mutations arise in patients during PML development.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Sangre/virología , Factores Inmunológicos/administración & dosificación , Virus JC/genética , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Leucoencefalopatía Multifocal Progresiva/virología , Sustitución de Aminoácidos/genética , Anticuerpos Monoclonales Humanizados , Proteínas de la Cápside/genética , ADN Viral/química , ADN Viral/genética , Humanos , Mutación Missense , Natalizumab , Análisis de Secuencia de ADNRESUMEN
Cripto is a cell surface protein highly expressed in certain solid tumors, and overexpression of Cripto protein is oncogenic. Cripto-1 protein is encoded by CRIPTO1 gene. CRIPTO3, a presumed pseudogene, has an open reading frame with six amino acid differences from Cripto-1. We show that CRIPTO3 mRNA is the CRIPTO message expressed in many cancer samples. A CRIPTO3 SAGE tag was found in several cancer SAGE libraries, while the CRIPTO1 tag was found in ES cell libraries. In vitro experiments indicate both Cripto-1 and Cripto-3 proteins are functional in the Nodal-dependent signal pathway. Our data indicate that CRIPTO3 is an expressed gene, particularly in certain cancers, and suggest a potentially novel mechanism of oncogenesis through activation of a retrogene.
Asunto(s)
Transformación Celular Neoplásica/genética , Factor de Crecimiento Epidérmico/genética , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Seudogenes , Secuencia de Aminoácidos , Línea Celular Tumoral , Proteínas Ligadas a GPI , Humanos , Péptidos y Proteínas de Señalización Intercelular , Datos de Secuencia Molecular , Transcripción GenéticaRESUMEN
Psoriasis is a common inflammatory skin disease caused by genetic and environmental factors, including bacterial and viral infections. Since the skin is in constant contact with commensal and pathogenic microorganisms, we examined well-supported psoriasis genetic linkage intervals to identify genes encoding innate immune pattern recognition proteins that may play a role in pathogenesis. Two peptidoglycan recognition proteins, Pglyrp3 and Pglyrp4, are localized to the Psors4 locus on chromosome 1q21 in a gene cluster known as the epidermal differentiation complex (EDC). We show that these genes are expressed in the skin as well as in germinal centers in the tonsil. We tested 13 SNPs in or near these genes for association with psoriasis in two independent patient collections: a family-based patient set comprised of 375 individuals from 101 families, and a case-control patient collection of 282 patients with moderate to severe psoriasis and 192 healthy controls. In the family-based analysis, several SNPs in the Pglyrp3-Pglyrp4 locus show association with psoriasis (0.01 < P < 0.05). Multiple-SNP haplotypes incorporating Pglyrp3 and Pglyrp4 SNPs also show significant association in the transmission disequilibrium test (TDT; P < 0.01). In the case-control test, none of the SNPs that we tested show association with psoriasis when analyzed in single-SNP or haplotype-based tests. The discordance between the TDT and case-control results suggests that the two populations are significantly different in disease etiology, that the polymorphism responsible for the Psors4 linkage is elsewhere in the Pglyrp locus, or that the causative Psors4 polymorphism is in a location near but not in the Pglyrp locus. These data are consistent with previous reports of association of psoriasis with genes on 1q21, and suggest a role for Pglyrps in skin biology.