RESUMEN
Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales/genética , Leucoencefalopatías/genética , Mutación , ARN Nucleolar Pequeño/genética , Adolescente , Adulto , Calcinosis/genética , Calcinosis/patología , Línea Celular , Enfermedades de los Pequeños Vasos Cerebrales/patología , Niño , Preescolar , Cromosomas Humanos Par 17 , Estudios de Cohortes , Quistes/genética , Quistes/patología , Exoma , Femenino , Ligamiento Genético , Genoma Humano , Humanos , Lactante , Leucoencefalopatías/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.