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
Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.