RESUMEN
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development.
Asunto(s)
Daño del ADN/genética , Mutación de Línea Germinal , Leucemia Linfocítica Crónica de Células B/genética , Proteínas de Unión al GTP Monoméricas/genética , Adulto , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/genética , Estudios de Cohortes , Hibridación Genómica Comparativa , Frecuencia de los Genes , Células HeLa , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Masculino , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/genética , Proteína 1 que Contiene Dominios SAM y HD , Adulto JovenRESUMEN
In forensic investigations, DNA profiles are routinely obtained from firearms evidence and alternative hypotheses may be proposed for consideration on the activity level. DNA profiles found to be consistent with the DNA profile of a specific individual could be a result of directly handling the firearm or other modes of transfer of DNA. Sixteen law-enforcement-owned firearms were evaluated with samples collected from the frame and slide area, the trigger and trigger guard area, and the front and rear sights after brief handling by laboratory personnel. Twenty-two out of forty-eight samples resulted in DNA profiles suitable for comparison, of which six resulted in likelihood ratios (LR) that demonstrated support for the hypothesis that included the brief handler as a contributor to the DNA profile obtained from the sample. Five of these samples were obtained from the frame and slide and one was from the trigger and trigger guard area. None of the DNA profiles obtained from the sights supported the inclusion of the brief handler as a contributor to the DNA profile. Gaining knowledge and supporting data on the nature of DNA profiles typically obtained from both owners and brief handlers can be useful for the purposes of evaluative reporting when considering results obtained from firearm evidence.