Alternative splicing: good and bad effects of translationally silent substitutions.
ABSTRACT Nucleotide variations that do not alter the protein-coding sequence have been routinely considered as neutral. In light of the developments we have seen over the last decade or so in the RNA processing and translational field, it would be proper when assessing these variants to ask if this change is neutral, good or bad. This question has been recently partly addressed by genome-wide in silico analysis but significantly fewer cases by laboratory experimental examples. Of particular relevance is the effect these mutations have on the pre-mRNA splicing pattern. In fact, alterations in this process may occur as a consequence of translationally silent mutations leading to the expression of novel splicing isoforms and/or loss of an existing one. This phenomenon can either generate new substrates for evolution or cause genetic disease when aberrant isoforms altering the essential protein function are produced. In this review we briefly describe the current understanding in the field and discuss emerging directions in the study of the splicing mechanism by integrating disease-causing splicing mutations and evolutionary changes.
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ABSTRACT: Since its discovery in the early days of splicing research, U1snRNP has been recognized as a crucial player in the early stages of the splicing process. In particular, binding of U1snRNP to the 5'splice site of exons is a fundamental step in the formation of the early splicing complex and directs the subsequent assembly of the functional spliceosome. In recent years, the way that the U1snRNP molecular complexes recognize real 5' ss sequences from a huge background of similar decoy sequences has been extensively studied. In this review, we will provide an account of the latest functional properties of U1snRNP as a splicing factor, its role in transcriptional and mRNA degradation processes, and how these properties can be exploited to act as prospective therapeutic or gene silencing strategies. Finally, we will discuss the latest experimental evidence that challenges the absolute requirement of U1snRNP presence for splicing to take place.RNA biology 7(4):412-9. · 5.56 Impact Factor
Article: Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients.[show abstract] [hide abstract]
ABSTRACT: Cystinuria is a rare autosomal inherited disorder characterized by impaired transport of cystine and dibasic aminoacids in the proximal renal tubule. Classically, cystinuria is classified as type I (silent heterozygotes) and non-type I (heterozygotes with urinary hyperexcretion of cystine). Molecularly, cystinuria is classified as type A (mutations on SLC3A1 gene) and type B (mutations on SLC7A9 gene). The goal of this study is to provide a comprehensive clinical, biochemical and molecular characterization of a cohort of 12 Portuguese patients affected with cystinuria in order to provide insight into genotype-phenotype correlations. We describe seven type I and five non-type I patients. Regarding the molecular classification, seven patients were type A and five were type B. In SLC3A1 gene, two large genomic rearrangements and 13 sequence variants, including four new variants c.611-2A>C; c.1136+44G>A; c.1597T (p.Y533N); c.*70A>G, were found. One large genomic rearrangement was found in SLC7A9 gene as well as 24 sequence variants including 3 novel variants: c.216C>T (p.C72C), c.1119G>A (p.S373S) and c.*82C>T. In our cohort the most frequent pathogenic mutations were: large rearrangements (33.3% of mutant alleles) and a missense mutation c.1400T>C (p.M467T) (11.1%). This report expands the spectrum of SLC3A1 and SLC7A9 mutations and provides guidance in the clinical implementation of molecular assays in routine genetic counseling of Portuguese patients affected with cystinuria.Clinical Genetics 01/2011; 81(1):47-55. · 3.13 Impact Factor