RESUMEN
BACKGROUND: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. OBJECTIVE: We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. METHODS: We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. RESULTS: Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. CONCLUSION: Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
Asunto(s)
Ataxia Telangiectasia/genética , Ataxia Telangiectasia/mortalidad , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Ataxia Telangiectasia/epidemiología , Ataxia Telangiectasia/fisiopatología , Proteínas de la Ataxia Telangiectasia Mutada , Niño , Preescolar , Estudios de Cohortes , Femenino , Francia/epidemiología , Genotipo , Humanos , Lactante , Recién Nacido , Leucemia/genética , Linfoma/genética , Masculino , Morbilidad , Mutación , Infecciones del Sistema Respiratorio/genética , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
The insertion of a DNA copy of its RNA genome into a chromosome of the host cell is mediated by the viral integrase with the help of mostly uncharacterized cellular cofactors. We have recently described that the transcriptional co-activator LEDGF/p75 strongly interacts with HIV-1 integrase. Here we show that interaction of HIV-1 integrase with LEDGF/p75 is important for viral replication. Using multiple approaches including two-hybrid interaction studies, random and directed mutagenesis, we could demonstrate that HIV-1 virus harboring a single mutation that disrupts integrase-LEDGF/p75 interaction, resulted in defective HIV-1 replication. Furthermore, we found that LEDGF/p75 tethers HIV-1 integrase to chromosomes and that this interaction may be important for the integration process and the replication of HIV-1.