Figure - available from: BioMed Research International
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(a) Schematic representation of the human β-globin gene and mRNA. The three cryptic GT splicing sites activated by the IVSI-6 mutation and the two consequent stop codons are indicated with different colours. The IVSI-6 mutation (T→C) is identified by a red star. (b) Genomic region containing the first and second exons of the human β-globin gene, in bold characters. The IVSI-6 mutation occurring at the sixth nucleotide of the first intron is shown in red. The coloured boxes indicate the three cryptic splicing sites activated by the mutation and the two consequent stop codons. The transcription and translation starting sites are also indicated.
Source publication
Mouse models that carry mutations causing thalassemia represent a suitable tool to test in vivo new mutation-specific therapeutic approaches. Transgenic mice carrying the β-globin IVSI-6 mutation (the most frequent in middle-east regions, and recurrent in Italy and Greece) are, at present, not available.
We report the production and characterizati...
Citations
... Lewis and colleagues were the first to successfully generate a humanized mouse model of b-thalassemia that expresses an aberrant splice variant by carrying common IVSII-654 b-thalassemia splicing mutation [76]. More recently, subsequent models were generated harboring additional splice-disrupting mutations [77,78]. Importantly, these models were useful not only for gaining further understanding of the molecular mechanisms involved with the disease, but also as a platform for testing splice-switching oligonucleotides (SSO) [79]. ...
Alternative splicing of pre-mRNA increases genetic diversity, and recent studies estimate that most human multiexon genes are alternatively spliced. If this process is not highly regulated and accurate, it leads to mis-splicing events, which may result in proteins with altered function. A growing body of work has implicated mis-splicing events in a range of diseases, including cancer, neurodegenerative diseases, and muscular dystrophies. Understanding the mechanisms that cause aberrant splicing events and how this leads to disease is vital for designing effective therapeutic strategies. In this review, we focus on advances in therapies targeting splicing, and highlight the animal models developed to recapitulate disease phenotypes as a model for testing these therapies.
β-Thalassemia is a genetic form of anemia due to mutations in the β-globin gene, that leads to ineffective and extramedullary erythropoiesis, abnormal red blood cells and secondary iron-overload. The severity of the disease ranges from mild to lethal anemia based on the residual levels of globins production. Despite being a monogenic disorder, the pathophysiology of β-thalassemia is multifactorial, with different players contributing to the severity of anemia and secondary complications. As a result, the identification of effective therapeutic strategies is complex, and the treatment of patients is still suboptimal. For these reasons, several models have been developed in the last decades to provide experimental tools for the study of the disease, including erythroid cell lines, cultures of primary erythroid cells and transgenic animals. Years of research enabled the optimization of these models and led to decipher the mechanisms responsible for globins deregulation and ineffective erythropoiesis in thalassemia, to unravel the role of iron homeostasis in the disease and to identify and validate novel therapeutic targets and agents. Examples of successful outcomes of these analyses include iron restricting agents, currently tested in the clinics, several gene therapy vectors, one of which was recently approved for the treatment of most severe patients, and a promising gene editing strategy, that has been shown to be effective in a clinical trial. This review provides an overview of the available models, discusses pros and cons, and the key findings obtained from their study.
