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Mutations in DCHS1 cause mitral valve prolapse

Abstract

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1,2,3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. Despite a clear heritable component, the genetic aetiology 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 homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA 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 aetiological 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.

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Figure 1: Pedigrees, mutation, and phenotype.
Figure 2: Zebrafish Dchs1b is required for atrioventricular canal development.
Figure 3: DCHS1 mutations result in diminished protein levels.
Figure 4: Dchs1 deficiency causes MVP and myxomatous degeneration in the adult mouse.
Figure 5: Developmental aetiology for MVP.

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Acknowledgements

This work was supported by the Fondation Leducq (Paris, France) Mitral Transatlantic Network of Excellence grant 07CVD04. MVP patient studies were supported by an Innovation in Clinical Research award of the Doris Duke Charitable Foundation, by an award of the Aetna Quality Care Research Fund, and by a gift from Rena M. Shulsky, New York, New York (S.A.S. and R.A.L.). Sequencing of the candidate region was performed at the Venter Institute through a grant from the National Heart Lung and Blood Institute Resequencing and Genotyping (RS&G) Service (S.A.S.). The work at MUSC was performed in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Collection of the MVP France cohort was supported by the French Society of Cardiology. Other funding sources: National Heart Lung and Blood Institute: R01HL122906-01 (A.W.), R01-HL33756 (R.R.M.), COBRE 1P30 GM103342 (R.R.M., R.A.N., A.W.), 8P20 GM103444-07 (R.R.M. and R.A.N.), R01-HL109004 (D.J.M.), R01-HL127692 (D.J.M., S.A.S., R.A.N., R.A.L.); RO1-HL095696 (D.R.M.), VA Merit Review BX002327 (D.R.M.); National Institute of Mental Health R00-MH095867 (M.E.T.) The Hassenfeld Scholar Program (D.J.M.); The March of Dimes (M.E.T.); M.G.H. Scholars Program (S.A.S., M.E.T.); American Heart Association: 09GRNT2060075 (A.W.), 11SDG5270006 (R.A.N.), 2261354 (D.J.M.), 15GRNT25080052 (R.A.N.); National Science Foundation: EPS-0903795 (R.R.M.); NHLBI K24 HL67434, R01HL72265 and R01HL109506 and the Ellison Foundation, Boston, MA (R.A.L.), Howard Hughes Medical Institute (K.D.I.), and a gift from Michael Zak (D.J.M.). Thanks to T. Brown (MUSC) for his guidance on MRI studies, C. Hanscom (M.G.H.) for assistance with genomic libraries, and E. Lim (H.M.S.) for contributions in interpreting the exome mutation data. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.

Author information

Authors and Affiliations

Authors

Contributions

R.D., M.L., C.S., C.J., M.P., X.J., J.-J.S., D.T., S.O., X.E., F.C., and S.A.S. participated in genetic analysis, sequencing and mutation cloning. R.D., F.N.D., L.A.F., T.L.T., H.L.M., L.F.-F., J.S., C.T., R.A.L., and A.H. participated in patient collection and phenotyping using echocardiography. D.S.P., S.N.L. and D.J.M. performed zebrafish and cell culture experiments. M.E.T., M.R.S., N.B.N., C.D., H.B. and C.C. performed bioinformatics and statistical analysis. A.C., P.C., and P.B. established human patient cell cultures and histology on human tissues. A.d.V., K.W., K.D.I., Y.M., K.S., A.W., T.M., K.T., R.R.M. and R.A.N. performed mouse embryo and knockout experiments and cell alignment and migration assays. X.N., A.-M.B., D.R.M., H.K. performed mouse in vivo imaging. R.D., D.J.M., R.A.L., R.A.N. and S.A.S. wrote the manuscript. R.A.L., A.H., S.A.S. and J.J.S. coordinated the Leducq Mitral Network.

Corresponding authors

Correspondence to Russell A. Norris or Susan A. Slaugenhaupt.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Measurement of endogenous and exogenous gene expression in D. rerio.

a, Corresponding representative embryos of each morpholino knockdown on the left, with close-up of heart on the right. b, To assess efficiency of morpholino knockdown, 20 embryos were collected 72 h after injection, mRNA was collected, and quantitative PCR was performed with three technical replicates. We demonstrate that morpholino (MO) knockdown of each indicated gene results in reduced mRNA expression, after normalization to beta-actin expression, compared to mock-injected controls (two-sided Student’s t-test). P values are noted on graphs. c, Western blotting of 20 pooled embryos injected with DCHS1 mRNA demonstrates the production of protein. Mutant mRNA refers to the compound mutant P197L/R2513H.

Extended Data Figure 2 Apbb1 is not expressed during cardiac morphogenesis.

Apbb1 RNA expression was analysed at E14.5 in sagittal sections using 2 separate antisense probes. Whereas strong cranial and neural expression is observed for Apbb1, no detectable cardiac expression or valve expression (arrow) is evident.

Extended Data Figure 3 Dachsous1b expression at the atrioventricular junction.

In situ hybridization reveals the presence of dchs1b in the atrioventricular canal (avc) at 54 hpf (a, b) and 72 hpf (c). The dchs1b expression is purple while a counterstain for cardiac tissue is brown (a). White arrows highlight the dchs1b signal in the atrioventricular canal.

Extended Data Figure 4 Dachsous1b knockdown alters atrioventricular ring markers.

In situ hybridization at 48 hpf and 72 hpf, as indicated, was performed for known atrioventricular ring markers. In contrast to WT (a) bmp4 expression is expanded into the ventricle at 48 hpf in dchs1 knockdown embryos at 48 hpf (b), spp1 and notch1b expression was largely unperturbed (cf), and has2 expression was not detected at 48 hpf, and is faint at 72 hpf in dchs1 knockdown, compared to identically handled and stained controls (il).

Extended Data Figure 5 Histopathology mitral valves.

Human posterior leaflets of control, Barlow’s with MVP, and DCHS1 p.R2330C were isolated, fixed and stained with Movat’s pentachrome. Leaflet thickening, elongation and myxomatous degeneration is observed in the Barlow’s and DCHS1 p.R2330C leaflets compared to controls. Expansion of the proteoglycan layer (blue) and disruption of the normal stratification of matrix boundaries is observed in the Barlow’s and DCHS1 p.R2330C leaflets. Blue, proteoglycan; yellow, collagen; black, elastin; red, fibrin or cardiac muscle. Scale bars, 0.5 cm.

Extended Data Figure 6 Protein expression of uncoupled mutations.

In order to determine which family 1 DCHS1 mutation is leading to the observed decrease in protein expression, constructs were generated that harboured only the p.P197L or the p.R2513H variant. Mutant refers to the double mutant P197L/R2513H construct. Western blot analyses from transfected HEK293 cells, three independent biological replicates, demonstrate that the p.R2513H mutation causes a significant decrease in DCHS1 protein expression, similar to that of the construct with both variants (mutant), suggesting pathogenicity. Percent difference in protein levels is depicted. Normalization of data was accomplished by qPCR specific to the transfected constructs. P values from the Student’s t-test are indicated in graphs.

Extended Data Figure 7 Cardiac function is not altered in Dchs1+/− mice.

M-mode analyses were performed to determine whether cardiac structure and/or function were perturbed in the Dchs1+/− mice. No statistically significant differences were observed in either cardiac structure or calculated cardiac function (n = 6 for each genotype). IVS, interventricular septum; d, diastole; s, systole; LVID, left ventricular internal dimension; LVPW, left ventricular posterior wall; EF, ejection fraction; FS, fractional shortening; LV, left ventricle.

Extended Data Figure 8 Dchs1 expression during cardiac development.

Top, RNA expression of Dchs1 was analysed during embryonic gestation (E11.5, E13.5, and E15.5) by section in situ hybridization. At E11.5 Dchs1 RNA (blue staining) expression is observed in the endocardium and mesenchyme of the superior and inferior cushions (sAVC and iAVC, respectively). A gradient pattern of expression is observed at this time point with more intense expression near the endocardium. At E13.5 and E15.5, a similar pattern is observed in the forming anterior and posterior mitral leaflets (AL and PL, respectively). Bottom, Dchs1 protein expression (red) is observed throughout cardiac development in the endothelial cells and interstitial cells of the developing valves. Dchs1 shows asymmetric expression in the valvular interstitial cell bodies around E15.5 (arrowheads). Dchs1 protein is also observed in the epicardium and atrioventricular sulcus (arrows). (Red Dchs1; green MF20; blue Hoescht).

Extended Data Figure 9 Dchs1 deficiency causes altered valvular interstitial cell patterning in vivo.

a, IHC for eGFP of postnatal day 0 (P0) lineage traced Wt1-Cre/Rosa-eGFP/Dchs1+/+ neonatal mice show epicardial-derived cells (EPDCs) migrating into the posterior leaflet as a sheet of cells directly under the endothelium of the atrialis. This normal patterning is perturbed in the Wt1-Cre/Rose-eGFP/Dchs1+/− mice. 3D reconstructions were used to examine all EPDCs in the posterior leaflet of both genotypes to obtain a complete fate map of these cells. b, c, Total volume of the leaflet is unchanged at this time point. However, the total volume of EPDCs as well as total EPDC cell number is significantly increased. There is a significant decrease in the number of non-EPDCs in the posterior leaflet with no overall change in total cell number. These data demonstrate that a minimum threshold of Dchs1 expression is required for normal migration of EPDCs into the posterior leaflet, normal patterning of this cell population, and cross-talk between EPDC and non-EPDC cell types in the valve. **P < 0.01. d, Isolated anterior mitral leaflet from fetal (E17.5) Dchs1+/+ , Dchs1+/− , and Dchs1−/− mice were used to quantify cellular alignment of valvular interstitial cells. Vector maps were generated from histological (haematoxylin and eosin) stains to show orientation and alignment of cells in relationship to each other. Boxes in each vector map panel are represented as zoomed images of regions within each of the valves to show cell orientation. e, Cell alignment and polarity were quantified as the number of cells that deviate >10 degrees from the proximal-distal (P–D) axis of the leaflet. 90% of the cells in Dchs1+/+ show proper alignment with each other and along this P–D axis. Haploinsufficiency (Dchs1+/− ) results in a 50% reduction in cell alignment, which is further reduced in Dchs1−/− (*P values < 0.01).

Extended Data Figure 10 Mice and MVP patients with Dchs1 deficiency exhibit migratory defects in vitro.

a, Posterior leaflets of P0 neonatal Dchs1+/+ and Dchs1+/− mice were explanted and interstitial cells were allowed to migrate out for 24 h. Dchs1+/− mice exhibit increased migration (black lines drawn from explants) coincident with loss of cell–cell contacts and N-cadherin expression at focal adhesions. Whereas N-cadherin expression (red) is found at the membrane at points of cell–cell contract in Dchs1+/+ valvular interstitial cells (arrows), this membrane expression is lost in the Dchs1+/− cells and is prominently expressed in the cytoplasm (arrows). Nuclei, blue. b, Migration assays using control and MVP patient (p.R2330C) valvular interstitial cells exhibit a similar affect as observed in the mouse cells whereby the p.R2330C cells exhibit an increase in migration. P values are indicated in graphs.

Supplementary information

Parasternal long-axis view of family 1 proband

This video shows posterior leaflet prolapse and dilated left-heart chambers. (MOV 1102 kb)

Zoomed view of thickened, prolapsing leaflet in family 1 proband.

This video shows thickened, prolapsing leaflet in family 1 proband. (MOV 684 kb)

Doppler color flow mapping of family proband 1

This video shows severe MR, increasing with prolapse throughout systole. (MOV 808 kb)

High-speed video of wild type (control injected) D. rerio heart at 72 hours post-fertilization (hpf).

At this stage the heart has looped and blood flow is unidirectional from the atrium (upper right) to the ventricle, and a constriction has formed at the junction between the atrium and ventricle. No regurgitation is evident. (AVI 6980 kb)

High-speed video of dchs1b morphant D. rerio heart at 72 hpf.

Hearts of dchs1b morphants fail to loop properly and there is regurgitation of blood from the ventricle (lower right) into the atrium (upper left). Concomitant with this phenotype, there is reduced constriction of the AV canal. (AVI 6833 kb)

Parasternal long axis view of adult (9-month old) Dchs1+/+ heart

This video shows normal mitral valve opening and closing. (MP4 16824 kb)

Parasternal long-axis view of adult (9-month old) Dchs1+/- heart

This video shows anterior and posterior leaflet thickening and posterior leaflet prolapse. Prolapse is most easily observed at frames: 149, 188, and 300 (MP4 16671 kb)

This video comprises 2 clips, which show 3D reconstructions of Dchs1+/+ 9, and Dchs1+/- 9-month old posterior leaflet

Each of the clips shown were obtained from the micro-MRI slices. (MP4 16062 kb)

AMIRA 3D reconstruction of Dchs1+/+, Dchs1+/-, and Dchs1-/- E17.5 mitral leaflets.

Respective 3D reconstructions are shown sequentially during the movie. Green=Anterior Leaflet, Blue =Posterior Leaflet. (MP4 23413 kb)

AMIRA 3D reconstruction of EPDC lineage trace in Dchs1+/+ and Dchs1+/- PO posterior mitral leaflets.

Respective 3D reconstructions are shown sequentially during the movie. Green=EPDC, Blue =non-EPDCs (MP4 16431 kb)

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Durst, R., Sauls, K., Peal, D. et al. Mutations in DCHS1 cause mitral valve prolapse. Nature 525, 109–113 (2015). https://doi.org/10.1038/nature14670

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