Primary cilia defects causing mitral valve prolapse

Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progress to mitral valve prolapse in the adult. DZIPping along to diagnosis Mitral valve prolapse is a common congenital abnormality that can cause severe complications. By combining studies of mitral valve development in mice with human genetic data, Toomer et al. found that mitral valve prolapse can be caused by abnormal cilia function. The authors tracked mitral valve development in mice from fetal life to adulthood and also performed genetic analysis of human patients with mitral valve prolapse, particularly one family with an inherited form of the disease. The affected members of this family had a mutation in DZIP1, a gene that regulates ciliogenesis, and mice with this mutation also developed mitral valve prolapse, supporting its pathogenic nature. Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1. A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

[1]  National Institute of General Medical Sciences , 2020, Definitions.

[2]  R. Levine,et al.  Mitral Valve Prolapse: A Disease of Valve and Ventricle. , 2018, Journal of the American College of Cardiology.

[3]  R. Kim,et al.  Myocardial Fibrosis in Patients With Primary Mitral Regurgitation With and Without Prolapse. , 2018, Journal of the American College of Cardiology.

[4]  Francesca N. Delling,et al.  New insights into mitral valve dystrophy: a Filamin-A genotype–phenotype and outcome study , 2018, European heart journal.

[5]  P. Howe,et al.  TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis , 2017, Science Signaling.

[6]  Yufeng Shen,et al.  Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands , 2017, Nature Genetics.

[7]  S. Body,et al.  A role for primary cilia in aortic valve development and disease , 2017, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  A. Perkins,et al.  Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease , 2017, Nature Genetics.

[9]  Willian A. da Silveira,et al.  Genomics pipelines and data integration: challenges and opportunities in the research setting , 2017, Expert review of molecular diagnostics.

[10]  K. Yutzey,et al.  Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease , 2017, Cardiovascular research.

[11]  Jianbo Wang,et al.  Sema6D acts downstream of bone morphogenetic protein signalling to promote atrioventricular cushion development in mice. , 2016, Cardiovascular research.

[12]  P. Kohl,et al.  Electron tomography of rabbit cardiomyocyte three-dimensional ultrastructure , 2016, Progress in biophysics and molecular biology.

[13]  E. Revenkova,et al.  Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway , 2016, Development.

[14]  Lluis Quintana-Murci,et al.  The mutation significance cutoff: gene-level thresholds for variant predictions , 2016, Nature Methods.

[15]  A. Goldstein,et al.  Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix , 2016, Development.

[16]  D. Stainier,et al.  Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish , 2015, Development.

[17]  Francesca N. Delling,et al.  Genetic association analyses highlight biological pathways underlying mitral valve prolapse , 2015, Nature Genetics.

[18]  R. Markwald,et al.  Cardiovascular Development and Disease Increased Infiltration of Extra-cardiac Cells in Myxomatous Valve Disease , 2022 .

[19]  Francesca N. Delling,et al.  Mutations in DCHS1 Cause Mitral Valve Prolapse , 2015, Nature.

[20]  Q. Jiang,et al.  GSK3β-Dzip1-Rab8 Cascade Regulates Ciliogenesis after Mitosis , 2015, PLoS biology.

[21]  Janan T. Eppig,et al.  Global genetic analysis in mice unveils central role for cilia in congenital heart disease , 2015, Nature.

[22]  John T. Walker,et al.  Comparative analysis of genes regulated by Dzip1/iguana and hedgehog in zebrafish , 2015, Developmental dynamics : an official publication of the American Association of Anatomists.

[23]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[24]  J. Schneider,et al.  Interrogation of living myocardium in multiple static deformation states with diffusion tensor and diffusion spectrum imaging , 2014, Progress in biophysics and molecular biology.

[25]  F. Spinale,et al.  Targeted Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-4 Modifies Post–Myocardial Infarction Remodeling in Mice , 2014, Circulation research.

[26]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[27]  Francesca N. Delling,et al.  Mild expression of mitral valve prolapse in the Framingham offspring: expanding the phenotypic spectrum. , 2014, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[28]  J. Lemasters,et al.  Cyclosporin A in left ventricular remodeling after myocardial infarction. , 2014, American journal of physiology. Heart and circulatory physiology.

[29]  Aimin Liu,et al.  Centrosomal Protein DZIP1 Regulates Hedgehog Signaling by Promoting Cytoplasmic Retention of Transcription Factor GLI3 and Affecting Ciliogenesis* , 2013, The Journal of Biological Chemistry.

[30]  L. Larsen,et al.  TGF-Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium , 2013 .

[31]  Gabrielle Wheway,et al.  The SYSCILIA gold standard (SCGSv1) of known ciliary components and its applications within a systems biology consortium , 2013, Cilia.

[32]  S. Vokes,et al.  Sonic hedgehog signaling directly targets Hyaluronic Acid Synthase 2, an essential regulator of phalangeal joint patterning. , 2013, Developmental biology.

[33]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[34]  M. Willaredt,et al.  Multiple essential roles for primary cilia in heart development , 2012, Cilia.

[35]  D. Zheng,et al.  Endocardial Cells Form the Coronary Arteries by Angiogenesis through Myocardial-Endocardial VEGF Signaling , 2012, Cell.

[36]  E. Golemis,et al.  The extracellular matrix and ciliary signaling. , 2012, Current opinion in cell biology.

[37]  C. Walsh,et al.  Developmental basis for filamin-A-associated myxomatous mitral valve disease. , 2012, Cardiovascular research.

[38]  R. Levine,et al.  Atrioventricular valve development: new perspectives on an old theme. , 2012, Differentiation; research in biological diversity.

[39]  R. Norris,et al.  Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart. , 2012, Developmental biology.

[40]  N. Katsanis,et al.  The ciliopathies: a transitional model into systems biology of human genetic disease. , 2012, Current opinion in genetics & development.

[41]  G. Walz,et al.  Inversin, Wnt signaling and primary cilia. , 2012, Differentiation; research in biological diversity.

[42]  M. Choma,et al.  Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation , 2012, Proceedings of the National Academy of Sciences.

[43]  K. Anderson,et al.  A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. , 2011, Human molecular genetics.

[44]  M. Goumans,et al.  Lack of Primary Cilia Primes Shear-Induced Endothelial-to-Mesenchymal Transition , 2011, Circulation research.

[45]  W. Marshall,et al.  Ciliogenesis: building the cell's antenna , 2011, Nature Reviews Molecular Cell Biology.

[46]  J. Kreiling,et al.  Notch signalling regulates left-right asymmetry through ciliary length control , 2010, Development.

[47]  A. Sidow,et al.  Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome , 2010, Proceedings of the National Academy of Sciences.

[48]  Suhua Chang,et al.  i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study , 2010, Nucleic Acids Res..

[49]  Sudipto Roy,et al.  The iguana/DZIP1 protein is a novel component of the ciliogenic pathway essential for axonemal biogenesis , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[50]  Suhua Chang,et al.  i-GSEA 4 GWAS : a web server for identification of pathways / gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study , 2010 .

[51]  P. Ingham,et al.  Gli2a protein localization reveals a role for Iguana/DZIP1 in primary ciliogenesis and a dependence of Hedgehog signal transduction on primary cilia in the zebrafish , 2010, BMC Biology.

[52]  M. Zile,et al.  Calpain inhibition preserves myocardial structure and function following myocardial infarction. , 2009, American journal of physiology. Heart and circulatory physiology.

[53]  Kim Van der Heiden,et al.  Primary cilia sensitize endothelial cells for fluid shear stress , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[54]  Beerend P. Hierck,et al.  The development of the heart and microcirculation: role of shear stress , 2008, Medical & Biological Engineering & Computing.

[55]  N. Katsanis,et al.  Ciliary function and Wnt signal modulation. , 2008, Current topics in developmental biology.

[56]  P. Satir,et al.  The primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair. , 2008, Current topics in developmental biology.

[57]  Amy E. Shyer,et al.  Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms , 2008, Nature Cell Biology.

[58]  P. Khatri,et al.  A systems biology approach for pathway level analysis. , 2007, Genome research.

[59]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[60]  I. Drummond,et al.  Notch signaling controls the differentiation of transporting epithelia and multiciliated cells in the zebrafish pronephros , 2007, Development.

[61]  W. Jackson,et al.  Intraflagellar transport is essential for endochondral bone formation , 2007, Development.

[62]  J. Trochu,et al.  Mutations in the Gene Encoding Filamin A as a Cause for Familial Cardiac Valvular Dystrophy , 2006, Circulation.

[63]  Ariel Linden What will it take for disease management to demonstrate a return on investment? New perspectives on an old theme. , 2006, The American journal of managed care.

[64]  Peter Satir,et al.  PDGFRαα Signaling Is Regulated through the Primary Cilium in Fibroblasts , 2005, Current Biology.

[65]  J. Marshall,et al.  New Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 13: Clinical Insights From Genetic Studies , 2005, Circulation.

[66]  Aimin Liu,et al.  Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors , 2005, Development.

[67]  P. Ingham,et al.  iguana encodes a novel zinc-finger protein with coiled-coil domains essential for Hedgehog signal transduction in the zebrafish embryo. , 2004, Genes & development.

[68]  H. Takeda,et al.  The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling , 2004, Development.

[69]  Gregor Eichele,et al.  GenePaint.org: an atlas of gene expression patterns in the mouse embryo , 2004, Nucleic Acids Res..

[70]  T. Laitinen,et al.  Mitral valve prolapse and mitral regurgitation are common in patients with polycystic kidney disease type 1. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[71]  G. Pazour,et al.  Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella , 2000, The Journal of cell biology.

[72]  T. Borg,et al.  Type I collagen synthesis in cultured human fibroblasts: regulation by cell spreading, platelet-derived growth factor and interactions with collagen fibers. , 1998, Matrix biology : journal of the International Society for Matrix Biology.

[73]  P. Gabow,et al.  Cardiovascular abnormalities in children with autosomal dominant polycystic kidney disease. , 1995, Journal of the American Society of Nephrology : JASN.

[74]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[75]  J. Marshall,et al.  Three-dimensional echocardiographic reconstruction of the mitral valve, with implications for the diagnosis of mitral valve prolapse. , 1989, Circulation.

[76]  A. Weyman,et al.  Reconsideration of Echocardiographic Standards for Mitral Valve Prolapse: Lack of Association Between Leaflet Displacement Isolated to the Apical Four Chamber View and Independent , 1988, Journal of the American College of Cardiology.

[77]  F. Ruddle,et al.  Gene transfer into mouse embryos: production of transgenic mice by pronuclear injection. , 1983, Methods in enzymology.