RESUMEN
Aicardi-Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/genética , Mutación Puntual , Sitios de Empalme de ARN , Ribonucleasa H/genética , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/enzimología , Femenino , Variación Genética , Humanos , Lactante , Recién Nacido , Masculino , Mutación Missense , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/enzimología , Ribonucleasa H/metabolismoRESUMEN
The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , ARN Helicasas DEAD-box/genética , Interferón Tipo I/inmunología , Modelos Moleculares , Mutación/genética , Malformaciones del Sistema Nervioso/genética , Fenotipo , Transducción de Señal/genética , Análisis de Varianza , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Secuencia de Bases , ARN Helicasas DEAD-box/química , Ensayo de Cambio de Movilidad Electroforética , Exoma/genética , Células HEK293 , Humanos , Helicasa Inducida por Interferón IFIH1 , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Malformaciones del Sistema Nervioso/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Análisis EspectralRESUMEN
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.