Mutations in DCHS1 Cause Mitral Valve Prolapse

SUMMARY Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1–3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. Morpholino knockdown of the zebrafish homolog dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 mRNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells, and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs as well as in Dchs1+/− mouse MVICs result in altered migration and cellular patterning, supporting these processes as etiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease

Hexafluoroisopropanol as a highly versatile solvent

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) has recently become a very popular solvent or additive with applications across the spectrum of chemistry. Analysis shows that it possesses a wide range of interesting and unique properties. In this Perspective, we detail the main uses of HFIP in the natural sciences and disclose the underlying principles that give it such wide appeal. Accordingly, we show the broad usage and beneficial effects in many areas of chemistry

Contemporary management of ureteral strictures

© 2018, British Association of Urological Surgeons 2018. Ureteral stricture disease is a luminal narrowing of the ureter leading to functional obstruction of the kidney. Treatment of strictures is mandatory to preserve and protect renal function. In recent times, the surgical management of ureteral strictures has evolved from open repair to include laparoscopic, robotic and interventional techniques. Prompt diagnosis and early first line intervention to limit obstructive complications remains the cornerstone of successful treatment. In this article, we discuss minimally invasive, endo-urological and open approaches to the repair of ureteral strictures. Open surgical repair and endoscopic techniques have traditionally been employed with varying degrees of success. The advent of laparoscopic and robotic approaches has reduced morbidity, improved cosmesis and shortened recovery time, with results that are beginning to mirror and in some cases surpass more traditional approaches. Level of evidence: Not applicable for this multicentre audit