Playing catching up: Proceedings of the 1 Spanish conference on genomic medicine.

On May 23-24, 2024, the 1 Spanish Conference on Genomic Medicine convened in Madrid, Spain. An international and multidisciplinary group of experts gathered to discuss the current state and prospects of genomic medicine in the Spanish-speaking world. There were 278 attendees from Latin America, US, UK, Germany, and Spain, and the topics covered included rare diseases, genome medicine in national health systems (NHSs), artificial intelligence, and commercial development ventures.

Therapeutic potential of oleic acid supplementation in myotonic dystrophy muscle cell models.

Background: We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed.

Msi2 enhances muscle dysfunction in a myotonic dystrophy type 1 mouse model.

Background: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the 3' untranslated region of the DM1 protein kinase gene. Characteristic degenerative muscle symptoms include myotonia, atrophy, and weakness. We previously proposed an Musashi homolog 2 (MSI2)>miR-7>autophagy axis whereby MSI2 overexpression repressed miR-7 biogenesis that subsequently de-repressed muscle catabolism through excessive autophagy.

Natural Compound Boldine Lessens Myotonic Dystrophy Type 1 Phenotypes in DM1 Drosophila Models, Patient-Derived Cell Lines, and HSA Mice.

Myotonic dystrophy type 1 (DM1) is a complex rare disorder characterized by progressive muscle dysfunction, involving weakness, myotonia, and wasting, but also exhibiting additional clinical signs in multiple organs and systems. Central dysregulation, caused by an expansion of a CTG trinucleotide repeat in the DMPK gene's 3' UTR, has led to exploring various therapeutic approaches in recent years, a few of which are currently under clinical trial. However, no effective disease-modifying treatments are available yet.

BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA Mice.

The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DM1 protein kinase () gene that, upon transcription, physically sequesters the Muscleblind-like (MBNL) family of splicing regulator proteins. The high-affinity binding occurring between the proteins and the repetitions disallow MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness.

Quantitative magnetic resonance imaging assessment of muscle composition in myotonic dystrophy mice.

Myotonic dystrophy type 1 (DM1) is a severe autosomal dominant neuromuscular disease in which the musculoskeletal system contributes substantially to overall mortality and morbidity. DM1 stems from a noncoding CTG trinucleotide repeat expansion in the DMPK gene. The human skeletal actin long repeat (HSA) mouse model reproduces several aspects of the disease, but the muscle-wasting phenotype of this model has never been characterized in vivo.

Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model.

Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase () gene. DM1 patients exhibit a pathogenic number of repetitions in , which leads to downstream symptoms.

Defined D-hexapeptides bind CUG repeats and rescue phenotypes of myotonic dystrophy myotubes in a Drosophila model of the disease.

In Myotonic Dystrophy type 1 (DM1), a non-coding CTG repeats rare expansion disease; toxic double-stranded RNA hairpins sequester the RNA-binding proteins Muscleblind-like 1 and 2 (MBNL1 and 2) and trigger other DM1-related pathogenesis pathway defects. In this paper, we characterize four D-amino acid hexapeptides identified together with abp1, a peptide previously shown to stabilize CUG RNA in its single-stranded conformation. With the generalized sequence cpy(a/t)(q/w)e, these related peptides improved three MBNL-regulated exon inclusions in DM1-derived cells.

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the gene. CUG expansions in mutant transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration.

Design of novel small molecule base-pair recognizers of toxic CUG RNA transcripts characteristics of DM1.

Myotonic Dystrophy type 1 (DM1) is an incurable neuromuscular disorder caused by toxic DMPK transcripts that carry CUG repeat expansions in the 3' untranslated region (3'UTR). The intrinsic complexity and lack of crystallographic data makes noncoding RNA regions challenging targets to study in the field of drug discovery. In DM1, toxic transcripts tend to stall in the nuclei forming complex inclusion bodies called foci and sequester many essential alternative splicing factors such as Muscleblind-like 1 (MBNL1).

Therapeutic Potential of AntagomiR-23b for Treating Myotonic Dystrophy.

Myotonic dystrophy type 1 (DM1) is a chronically debilitating, rare genetic disease that originates from an expansion of a noncoding CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene. The expansion becomes pathogenic when DMPK transcripts contain 50 or more repetitions due to the sequestration of the muscleblind-like (MBNL) family of proteins. Depletion of MBNLs causes alterations in splicing patterns in transcripts that contribute to clinical symptoms such as myotonia and muscle weakness and wasting.

miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models.

Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells.

Myotonic dystrophy: candidate small molecule therapeutics.

Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family.

Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes.

Myotonic dystrophies (DM1-2) are neuromuscular genetic disorders caused by the pathological expansion of untranslated microsatellites. DM1 and DM2, are caused by expanded CTG repeats in the 3'UTR of the DMPK gene and CCTG repeats in the first intron of the CNBP gene, respectively. Mutant RNAs containing expanded repeats are retained in the cell nucleus, where they sequester nuclear factors and cause alterations in RNA metabolism.

In silico discovery of substituted pyrido[2,3-d]pyrimidines and pentamidine-like compounds with biological activity in myotonic dystrophy models.

Myotonic dystrophy type 1 (DM1) is a rare multisystemic disorder associated with an expansion of CUG repeats in mutant DMPK (dystrophia myotonica protein kinase) transcripts; the main effect of these expansions is the induction of pre-mRNA splicing defects by sequestering muscleblind-like family proteins (e.g. MBNL1).

Six Serum miRNAs Fail to Validate as Myotonic Dystrophy Type 1 Biomarkers.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease caused by expansion of a CTG microsatellite in the 3' untranslated region of the DMPK gene. Despite characteristic muscular, cardiac, and neuropsychological symptoms, CTG trinucleotide repeats are unstable both in the somatic and germinal lines, making the age of onset, clinical presentation, and disease severity very variable. A molecular biomarker to stratify patients and to follow disease progression is, thus, an unmet medical need.

Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction.

Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage of varying degrees. Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. Despite its importance, very few animal model studies have focused on the heart dysfunction in DM1.

Development of a Drosophila melanogaster spliceosensor system for in vivo high-throughput screening in myotonic dystrophy type 1.

Alternative splicing of pre-mRNAs is an important mechanism that regulates cellular function in higher eukaryotes. A growing number of human genetic diseases involve splicing defects that are directly connected to their pathology. In myotonic dystrophy type 1 (DM1), several clinical manifestations have been proposed to be the consequence of tissue-specific missplicing of numerous genes.

In vivo strategies for drug discovery in myotonic dystrophy disorders.

Myotonic dystrophy (DM) is a complex neuromuscular genetic disease for which there is currently no valid therapy. The recent development of non-mammal animal models opened up the possibility of performing drug discovery in vivo, using as screening readout phenotypes with underlying molecular parallels to the disease. In this review we discuss the state of the art technologies already used in large scale drug screening and provide guidance for further development of novel technologies.

Nemo regulates cell dynamics and represses the expression of miple, a midkine/pleiotrophin cytokine, during ommatidial rotation.

Ommatidial rotation is one of the most important events for correct patterning of the Drosophila eye. Although several signaling pathways are involved in this process, few genes have been shown to specifically affect it. One of them is nemo (nmo), which encodes a MAP-like protein kinase that regulates the rate of rotation throughout the entire process, and serves as a link between core planar cell polarity (PCP) factors and the E-cadherin-β-catenin complex.

Expanded CTG repeats trigger miRNA alterations in Drosophila that are conserved in myotonic dystrophy type 1 patients.

Myotonic dystrophy type 1 (DM1) is caused by the expansion of CTG repeats in the 3' untranslated region of the DMPK gene. Several missplicing events and transcriptional alterations have been described in DM1 patients. A large number of these defects have been reproduced in animal models expressing CTG repeats alone.

Case report: first successful application of preimplantation genetic diagnosis for hereditary angiooedema.

Hereditary angiooedema is an autosomal dominant disease caused by mutations in the SERPING1 gene. It is characterized by oedemas in different parts of the body, being particularly dangerous when swelling involves the upper airway. Preimplantation genetic diagnosis (PGD) was performed in a couple where the woman carries a deletion of 2.

Prevalence of atrial fibrillation and use of antithrombotics in hypertensive patients aged >or=65 years. The FAPRES trial.

Introduction And Objectives: Age and arterial hypertension are two of the main factors associated with atrial fibrillation and an increased risk of embolism. The objective of this study was to determine the prevalence of atrial fibrillation and the extent of antithrombotic use in hypertensive patients aged >or=65 years in the Spanish region of Valencia.

Methods: Each study investigator enrolled the first three hypertensive patients aged >or=65 years who came for a consultation on the first day of each week for 5 weeks.

Prevalencia de fibrilación auricular y uso de fármacos antitrombóticos en el paciente hipertenso ≥ 65 años. El registro FAPRES.

Introduction And Objectives: Age and arterial hypertension are two of the main factors associated with atrial fibrillation and an increased risk of embolism. The objective of this study was to determine the prevalence of atrial fibrillation and the extent of antithrombotic use in hypertensive patients aged ≥65 years in the Spanish region of Valencia.

Methods: Each study investigator enrolled the first three hypertensive patients aged ≥65 years who came for a consultation on the first day of each week for 5 weeks.

Successful application of preimplantation genetic diagnosis for hypokalaemic periodic paralysis.

Hypokalaemic periodic paralysis is a rare dominant inherited disease where a person suffers sudden falls of circulating potassium concentrations, producing muscle weakness and sometimes severe paralysis. Attacks can occur as frequently as several times a day or once in a year. The age of onset is usually adolescence but symptoms can appear as early as 10 years of age.