Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus “cis” sequences that define exon-intron boundaries and regulatory sequences recognized by splicing machinery. Point mutations at these consensus sequences can cause improper exon and intron recognition and may result in the formation of an aberrant transcript of the mutated gene. The splicing mutation may occur in both introns and exons and disrupt existing splice sites or splicing regulatory sequences (intronic and exonic splicing silencers and enhancers), create new ones, or activate the cryptic ones. Usually such mutations result in errors during the splicing process and may lead to improper intron removal and thus cause alterations of the open reading frame. Recent research has underlined the abundance and importance of splicing mutations in the etiology of inherited diseases. The application of modern techniques allowed to identify synonymous and nonsynonymous variants as well as deep intronic mutations that affected pre-mRNA splicing. The bioinformatic algorithms can be applied as a tool to assess the possible effect of the identified changes. However, it should be underlined that the results of such tests are only predictive, and the exact effect of the specific mutation should be verified in functional studies. This article summarizes the current knowledge about the “splicing mutations” and methods that help to identify such changes in clinical diagnosis.

/pdf/splicing-mutations-in-human-genetic-disorders-examples-aq1juedgsc.pdf

Splicing mutations in human genetic disorders: examples, detection, and confirmation.

Most genes are processed by alternative splicing for gene expression, resulting in the complexity of the transcriptome in eukaryotes It allows a limited number of genes to encode various proteins with intricate functions Alternative splicing is regulated by genetic mutations in cis-regulatory factors and epigenetic events Furthermore, splicing events occur differently according to cell type, developmental stage, and various diseases, including cancer Genome instability and flexible proteomes by alternative splicing could affect cancer cells to grow and survive, leading to metastasis Cancer cells that are transformed by aberrant and uncontrolled mechanisms could produce alternative splicing to maintain and spread them continuously Splicing variants in various cancers represent crucial roles for tumorigenesis Taken together, the identification of alternative spliced variants as biomarkers to distinguish between normal and cancer cells could cast light on tumorigenesis

/pdf/alternative-splicing-and-its-impact-as-a-cancer-diagnostic-2yhj7ghiy2.pdf

Alternative splicing and its impact as a cancer diagnostic marker.

Aberrant and alternative splicing in skeletal system disease.

IgE recognition of chimeric isoforms of the honeybee (Apis mellifera) venom allergen Api m 10 evaluated by protein array technology.

Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive osteochondrodysplasia characterized by disproportionately short stature and degenerative joint disease. The objective of this study was to describe a novel nonsense mutation in the sedlin gene (SEDL) causing severe SEDT in a large Chinese pedigree. The clinical features of all affected individuals and female carriers were presented. Four affected males of the family were diagnosed with SEDT according to their clinical and radiological features. Direct DNA sequencing of SEDL was performed. Reverse-transcription polymerase chain reaction (RT-PCR) experiments of total RNA from blood lymphocytes were performed to confirm the defect in SEDL. DNA sequencing revealed that all of the affected males carried a nonsense mutation (c.61G>T) in SEDL that has not been previously reported. The c.61G>T mutation resulted in a premature translation termination codon (GAG>TAG) at amino acid position 21 (p.E21*), and was predicted to initiate the degradation of mutant transcripts through the nonsense-mediated mRNA decay pathway. Two female carriers showed typical sequencing chromatograms of a heterozygote. Following genetic counseling, individual IV7 gave birth to a healthy baby. Therefore, identification of the novel nonsense mutation (c.61G>T) in the SEDT family enables carrier detection, genetic counseling, and prenatal diagnosis. The detailed genotype/phenotype descriptions contribute to the SEDL mutation spectrum. The continued identification of mutations in SEDT patients will greatly aid further elucidation of the role of the sedlin protein in normal bone growth.

/pdf/a-novel-nonsense-mutation-in-the-sedlin-gene-sedl-causes-4hm77to2cc.pdf

A novel nonsense mutation in the sedlin gene (SEDL) causes severe spondyloepiphyseal dysplasia tarda in a five-generation Chinese pedigree.

X-linked spondyloepiphyseal dysplasia tarda can be caused by mutations in the SEDL gene. This study describes an interesting novel mutation (IVS4+1A>G) located exactly at the rare noncanonical AT–AC consensus splicing donor point of SEDL, which regained the canonical GT–AG consensus splicing junction in addition to several other rarer noncanonical splice patterns. The mutation activated several cryptic splice sites and generated the production of seven erroneous splicing isoforms, which we confirmed by sequencing of RT-PCR products and resequencing of cDNA clones. All the practical splice donors/acceptors were further assessed using FSPLICE 1.0 and SPL(M) Platforms to predict potential splice sites in genomic DNA. Subsequently, the expression levels of SEDL among the affected patients, carriers and controls were estimated using real-time quantitative PCR. Expression analyses showed that the expression levels of SEDL in both patients and carriers were decreased. Taken together, these results illustrated how disruption of the AT donor site in a rare AT–AC intron, leading to a canonical GT donor site, resulted in a multitude of aberrant transcripts, thus impairing exon definition. The unexpected splicing patterns resulting from the special mutation provide additional challenges and opportunities for understanding splicing mechanisms and specificity.

/pdf/noncanonical-and-canonical-splice-sites-a-novel-mutation-at-1lyyejnmm4.pdf

Noncanonical and canonical splice sites: a novel mutation at the rare noncanonical splice-donor cut site (IVS4+1A>G) of SEDL causes variable splicing isoforms in X-linked spondyloepiphyseal dysplasia tarda

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Noncanonical and canonical splice sites: a novel mutation at the rare noncanonical splice-donor cut site (IVS4+1A>G) of SEDL causes variable splicing isoforms in X-linked spondyloepiphyseal dysplasia tarda