Analysis of SRrp86-regulated alternative splicing: control of c-Jun and IκBß activity.

Previous work led to the hypothesis that SRrp86, a related member of the SR protein superfamily, can interact with and modulate the activity of other SR proteins. Here, we sought to test this hypothesis by examining the effect of changing SRrp86 concentrations on overall alternative splicing patterns. SpliceArrays were used to examine 9,854 splicing events in wild-type cells, cells overexpressing SRrp86, and cells treated with siRNAs to knockdown SRrp86. From among the 500 splicing events exhibiting altered splicing under these conditions, the splicing of c-Jun and IκBß were validated as being regulated by SRrp86 resulting in altered regulation of their downstream targets. In both cases, functionally distinct isoforms were generated that demonstrate the role SRrp86 plays in controlling alternative splicing.

Splicing fidelity, enhancers, and disease.

Eukaryotic pre-mRNA splicing allows for a large, diverse proteome to be coded by a relatively small genome. Alternative splicing events are well regulated, but when mutations disrupt the splice sites or regulatory elements, disease can occur. Similarly, mutations can cause disease through aberrant transcript production. Enhancers, one of the splicing regulatory elements, are frequent targets of disease causing mutations. This review provides an overview of the splicing reaction and mechanisms of alternative splicing and provides examples of enhancer defects that cause disease.

A targeted approach to reducing overutilization: use of percutaneous coronary intervention in stable coronary artery disease.

Overutilization, defined as use of unnecessary care when alternatives may produce similar outcomes, results in higher cost without increased value. Overutilization can be understood by focusing on settings where overuse is obvious. One example is percutaneous coronary intervention (PCI) in chronic stable angina. PCI is a potentially lifesaving procedure in an acute setting, but current practice guidelines indicate low-risk patients with chronic stable angina should be treated initially with optimal medical therapy (OMT) and lifestyle modification. A decision to move from this approach to PCI should be based on severity of symptoms and degree of risk. Over the last 30 years, advances in equipment, adjunctive medical treatments, and safety have made PCI more common. Recent evidence questions the benefit of PCI in stable coronary artery disease demonstrating no reduction in overall mortality or major cardiac events compared to OMT. Despite these findings, some continue to favor aggressive PCI interventions over conservative management in low-risk situations. Patients who undergo PCI without understanding the evidence may be inappropriately reassured that PCI will reduce the need for OMT and the risk of heart attack and death. Research shows shared decision-making can result in more conservative care, particularly when patients are assessed for health literacy and counseled on clinical evidence. Overutilization of PCI can be addressed by promoting active participation in an evidence-based decision-making process, allowing the opportunity to understand the expected value of invasive procedures over OMT alone through processes that encourage physicians to incorporate shared decision making prior to PCI in non-acute situations.

Conservative spine care: opportunities to improve the quality and value of care.

Low back pain (LBP) has received considerable attention from researchers and health care systems because of its substantial personal, social, work-related, and economic consequences. A narrative review was conducted summarizing data about the epidemiology, care seeking, and utilization patterns for LBP in the adult US population. Recommendations from a consensus of clinical practice guidelines were compared to findings about the current state of clinical practice for LBP. The impact of the first provider consulted on the quality and value of care was analyzed longitudinally across the continuum of episodes of care. The review concludes with a description of recently published evidence that has demonstrated that favorable health and economic outcomes can be achieved by incorporating evidence-informed decision criteria and guidance about entry into conservative low back care pathways.

Growth hormone deficiency and splicing fidelity: two serine/arginine-rich proteins, ASF/SF2 and SC35, act antagonistically.

The majority of mutations that cause isolated growth hormone deficiency type II are the result of aberrant splicing of transcripts encoding human growth hormone. Such mutations increase skipping of exon 3 and encode a 17.5-kDa protein that acts as a dominant negative to block secretion of full-length protein produced from unaffected alleles. Previously, we identified a splicing regulatory element in exon 3 (exonic splicing enhancer 2 (ESE2)), but we had not determined the molecular mechanism by which this element prevents exon skipping. Here, we show that two members of the serine/arginine-rich (SR) protein superfamily (ASF/SF2 and SC35) act antagonistically to regulate exon 3 splicing. ASF/SF2 activates exon 3 inclusion, but SC35, acting through a region just downstream of ESE2, can block such activation. These findings explain the disease-causing mechanism of a patient mutation in ESE2 that creates a functional SC35-binding site that then acts synergistically with the downstream SC35 site to produce pathological levels of exon 3 skipping. Although the precedent for SR proteins acting as repressors is established, this is the first example of a patient mutation that creates a site through which an SR protein represses splicing.