RESUMEN
The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
Asunto(s)
Adenosina Desaminasa/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Proteínas de Unión al ARN/genética , Convulsiones/genética , Alelos , Empalme Alternativo/genética , Niño , Preescolar , Células HEK293 , Humanos , Masculino , Empalme del ARN/genéticaRESUMEN
Transposable elements (TEs) have been shown to have important gene regulatory functions and their alteration could lead to disease phenotypes. Acute myeloid leukemia (AML) develops as a consequence of a series of genetic changes in hematopoietic precursor cells, including mutations in epigenetic factors. Here, we set out to study the gene regulatory role of TEs in AML. We first explored the epigenetic landscape of TEs in AML patients using ATAC-seq data. We show that a large number of TEs in general, and more specifically mammalian-wide interspersed repeats (MIRs), are more enriched in AML cells than in normal blood cells. We obtained a similar finding when analyzing histone modification data in AML patients. Gene Ontology enrichment analysis showed that genes near MIRs in open chromatin regions are involved in leukemogenesis. To functionally validate their regulatory role, we selected 19 MIR regions in AML cells, and tested them for enhancer activity in an AML cell line (Kasumi-1) and a chronic myeloid leukemia (CML) cell line (K562); the results revealed several MIRs to be functional enhancers. Taken together, our results suggest that TEs are potentially involved in myeloid leukemogenesis and highlight these sequences as potential candidates harboring AML-associated variation.
Asunto(s)
Elementos Transponibles de ADN/genética , Elementos de Facilitación Genéticos/genética , Regulación Leucémica de la Expresión Génica/genética , Leucemia Mieloide Aguda/genética , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Cromatina/genética , Ontología de Genes , Genoma Humano , Humanos , Ratones , Modelos Biológicos , Motivos de Nucleótidos , Factores de TranscripciónRESUMEN
The purpose of this review article is to evaluate the current method of sonographic measurement of ovarian volume as a means of diagnosing ovarian tumors in postmenopausal women, in whom an ovarian volume greater than 10 ml is generally considered abnormal. After reviewing the general medical literature, we propose a nomogram of ovarian volume that may be used to determine whether an ovary is abnormal. Furthermore, on the basis of our previous results, we recommend that a cutoff point for ovarian volume that is adjusted to patient age be used to determine whether an ovary is abnormal. We recommend the use of such nomograms in routine clinical practice to assist physicians in identifying abnormality of the ovaries during sonographic examination.