Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.(1,2) We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1(+/-) mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE

Profundización en metodologías y espacios docentes innovadores

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Eukaryotic penelope-like retroelements encode hammerhead ribozyme motifs

[EN] Small self-cleaving RNAs, such as the paradigmatic Hammerhead ribozyme (HHR), have been recently found widespread in DNA genomes across all kingdoms of life. In this work, we found that new HHR variants are preserved in the ancient family of Penelope-like elements (PLEs), a group of eukaryotic retrotransposons regarded as exceptional for encoding telomerase-like retrotranscriptases and spliceosomal introns. Our bioinformatic analysis revealed not only the presence of minimalist HHRs in the two flanking repeats of PLEs but also their massive and widespread occurrence in metazoan genomes. The architecture of these ribozymes indicates that they may work as dimers, although their low self-cleavage activity in vitro suggests the requirement of other factors in vivo. In plants, however, PLEs show canonical HHRs, whereas fungi and protist PLEs encode ribozyme variants with a stable active conformation as monomers. Overall, our data confirm the connection of self-cleaving RNAs with eukaryotic retroelements and unveil these motifs as a significant fraction of the encoded information in eukaryotic genomes.This work was supported by the Ministerio de Economia y Competitividad (grant number BFU2011-23398).Cervera Olagüe, A.; La Peña Del Rivero, MD. (2014). Eukaryotic penelope-like retroelements encode hammerhead ribozyme motifs. Molecular Biology and Evolution. 31(11):2941-2947. https://doi.org/10.1093/molbev/msu232S29412947311

Meeting Point: methods and spaces for the flipped classroom

Desarrollo de programas formativos centrados en los estudiantes gracias a la mejora de la calidad de los recursos materiales y del personal docente e investigador.Vicerrectorado de CalidadFac. de FilologíaFALSEsubmitte

A Singular and Widespread Group of Mobile Genetic Elements: RNA Circles with Autocatalytic Ribozymes

© 2020 by the authors.Circular DNAs, such as most prokaryotic and phage genomes, are a frequent form of nucleic acids, whereas circular RNAs had been regarded as unusual macromolecules until very recently. The first reported RNA circles were the family of small infectious genomes of viroids and circular RNA (circRNA) satellites of plant viruses, some of which contain small self-cleaving RNA motifs, such as the hammerhead (HHR) and hairpin ribozymes. A similar infectious circRNA, the unique human hepatitis delta virus (HDV), is another viral satellite that also encodes self-cleaving motifs called HDV ribozymes. Very recently, different animals have been reported to contain HDV-like circRNAs with typical HDV ribozymes, but also conserved HHR motifs, as we describe here. On the other hand, eukaryotic and prokaryotic genomes encode sequences able to self-excise as circRNAs, like the autocatalytic Group I and II introns, which are widespread genomic mobile elements. In the 1990s, the first circRNAs encoded in a mammalian genome were anecdotally reported, but their abundance and importance have not been unveiled until recently. These gene-encoded circRNAs are produced by events of alternative splicing in a process generally known as backsplicing. However, we have found a second natural pathway of circRNA expression conserved in numerous plant and animal genomes, which efficiently promotes the accumulation of small non-coding RNA circles through the participation of HHRs. Most of these genome-encoded circRNAs with HHRs are the transposition intermediates of a novel family of non-autonomous retrotransposons called retrozymes, with intriguing potential as new forms of gene regulation.This research was funded by the Ministerio de Economía y Competitividad of Spain and FEDER funds (BFU2017-87370-P).Peer reviewe

The Hammerhead Ribozyme: A Long History for a Short RNA

Small nucleolytic ribozymes are a family of naturally occurring RNA motifs that catalyse a self-transesterification reaction in a highly sequence-specific manner. The hammerhead ribozyme was the first reported and the most extensively studied member of this family. However, and despite intense biochemical and structural research for three decades since its discovery, the history of this model ribozyme seems to be far from finished. The hammerhead ribozyme has been regarded as a biological oddity typical of small circular RNA pathogens of plants. More recently, numerous and new variations of this ribozyme have been found to inhabit the genomes of organisms from all life kingdoms, although their precise biological functions are not yet well understood