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

OCT4-mediated inflammation induces cell reprogramming at the origin of cardiac valve development and calcification

International audienceCell plasticity plays a key role in embryos by maintaining the differentiation potential of progenitors. Whether postnatal somatic cells revert to an embryonic-like naïve state regaining plasticity and redifferentiate into a cell type leading to a disease remains intriguing. Using genetic lineage tracing and single-cell RNA sequencing, we reveal that Oct4 is induced by nuclear factor κB (NFκB) at embyronic day 9.5 in a subset of mouse endocardial cells originating from the anterior heart forming field at the onset of endocardial-to-mesenchymal transition. These cells acquired a chondro-osteogenic fate. OCT4 in adult valvular aortic cells leads to calcification of mouse and human valves. These calcifying cells originate from the Oct4 embryonic lineage. Genetic deletion of Pou5f1 (Pit-Oct-Unc, OCT4) in the endocardial cell lineage prevents aortic stenosis and calcification of ApoE−/− mouse valve. We established previously unidentified self-cell reprogramming NFκB- and OCT4-mediated inflammatory pathway triggering a dose-dependent mechanism of valve calcification

OCT4-mediated inflammation induces cell reprogramming at the origin of cardiac valve development and calcification

International audienceCell plasticity plays a key role in embryos by maintaining the differentiation potential of progenitors. Whether postnatal somatic cells revert to an embryonic-like naïve state regaining plasticity and redifferentiate into a cell type leading to a disease remains intriguing. Using genetic lineage tracing and single-cell RNA sequencing, we reveal that Oct4 is induced by nuclear factor κB (NFκB) at embyronic day 9.5 in a subset of mouse endocardial cells originating from the anterior heart forming field at the onset of endocardial-to-mesenchymal transition. These cells acquired a chondro-osteogenic fate. OCT4 in adult valvular aortic cells leads to calcification of mouse and human valves. These calcifying cells originate from the Oct4 embryonic lineage. Genetic deletion of Pou5f1 (Pit-Oct-Unc, OCT4) in the endocardial cell lineage prevents aortic stenosis and calcification of ApoE−/− mouse valve. We established previously unidentified self-cell reprogramming NFκB- and OCT4-mediated inflammatory pathway triggering a dose-dependent mechanism of valve calcification

Tests of the broadband borehole seismic system (B³S²) at Scripps IGPP and the Pinon Flat Observatory : October 1994 to June 1995

The broadband borehole seismic system (B3S2) is being developed as one component of the Ocean Seismic Network (OSN) Pilot Experiment which will be carried out at the OSN-1 Site off Hawaii in Winter 1998. The other major instruments being developed for the experiment are a Broadband Ocean Bottom Seismometer and a Shallow Buried Broadband Ocean Bottom Seismometer. B3S2 consists of four major components: 1) a borehole sonde with a re-entry guide, Teledyne 54000 broadband seismometer, and REFTEK digitizing system, 2) a seafloor acquisition and recording system (SEABASS), 3) a control vehicle for deploying the sonde in a borehole, and 4) shipboard command and control electronics. The deployment system is very similar to the SEABASS configuration used on LFASE (Stephen eta!, 1994). The purposes of the tests at Pinon Flat were: 1) to integrate the borehole sonde and seafloor and shipboard electronics which had been constructed by different groups: WHOI and SIO/IGPP; 2) test the combined subsystem in a wet borehole environment using actual cables and simulating seafloor conditions; and 3) acquire seismic ambient noise and earthquake data over approximately a three month period for comparison with known stations at the Pinon Flat Observatory.This work was carried out under NSF Grants No. OCE-91-18943 and OCE No. OCE-95-05730: "A Broadband Borehole Seismometer for the Deep Ocean - Development and Land Testing

Broadband borehole seismic system integration tests : report of the system integration tests at MPL/SIO

This report describes a series of tests performed at SIO/MPL, Point Lorna the week of 17 November 1997 designed to achieve integration of the Broadband Borehole Seismic System (BBBSS) in preparation for the OSN Pilot Experiment cruise on RN Thompson during January 1997. Representatives from all groups were present (see appendix A), with their respective parts of the system and support equipment. It was anticipated that these tests would result in the complete integration of the various components of the borehole seismometer system in preparation for the January cruise. The system would be assembled and tested following a plan (see appendix C) that would culminate in the fully integrated borehole seismometer being wet tested off the MPL pier.This work is sponsored by the National Science Foundation Grant Nos. OCE 9522114and OCE 9523541 with additional support from Scripps Institute of Oceanography and Woods Hole Oceanographic Institutio

Progress report on the development of the seafloor borehole array seismic system (phase II) : July 14, 1992 to January 31, 1996

The Seafloor Borehole Array Seismic System (SEABASS) was originally developed to record autonomously on the seafloor the signals received on a four-sonde three-component borehole geophone array in the VLF band (2-50Hz)(Stephen eta!., 1994). The system is designed to use the wireline re-entry capability (Spiess, 1993; Spiess eta!., 1992) to install and retrieve the seafloor instrumentation (Figures 1 and 2). Following the successful demonstration of this technology on the LFASE (Low Frequency Acoustic-Seismic Experiment) project in September 1989, it was decided to extend the capability to broadband (1000sec-5Hz) borehole seismometers which could be used for permanent seafloor seismic observatories in the Ocean Seismic Network (Orcutt and Stephen, 1993; Purdy and Dziewonski, 1988; Purdy and Orcutt, 1995; Stephen, 1995; Sutton and Barstow, 1990; Sutton eta!., 1988; Sutton eta!., 1965). The Broadband Borehole Seismic System (B3S2) is the prototype system for permanent broadband borehole seismic observatories on the seafloor. It has three major components: i) a broadband borehole seismometer, the Teledyne 54000, modified for seafloor operations by Scripps-IGPP; ii) the re-entry system provided by Scripps-MPL; and iii) the seafloor recording system developed by WHO I. Because of the similarity of the seafloor recording system to SEABASS we have named this new system SEABASS-ll. This report discusses the development of SEABASS-Il at WHOI in the period from July 14, 1992 to January 31, 1996. The motivation for the project and a work statement are contained in WHOI proposals 7016 and 7016.1. This report is a collection of documentation prepared while the work was being carried out. Some of the issues discussed in early memos were subsequently changed. Modifications and further testing of SEABASS-ll, as well as final system integration tests with the borehole andreentry systems (both of which are also still being modified and tested) have still to be carried out in preparation for the OSN Pilot Experiment Cruise in Spring 1997. This is a preliminary report only and presents work in progress. It will be useful to the engineering team as a historical reference of the sequence of events in the development of SEABASS-ll but it should not be considered as a technical manual for the instrumentation