Non-syndromal mitral valve prolapse (MVP): a common entity, but not commonly associated with DCHS1 or FLNA mutations.
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ABSTRACT:
SUBMITTER: Uphoff K
PROVIDER: S-EPMC9264077 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. 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.
| S-EPMC4720389 | biostudies-literature
Project description:BackgroundA recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation.MethodsDNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico.Resultsp.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases.ConclusionThis study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk.
| S-EPMC5823682 | biostudies-literature
Project description:Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.
| S-EPMC8874669 | biostudies-literature
Project description:Aim: Test the hypothesis that 5HT receptors (5HTRs) signaling contributes to MVP pathophysiology. Methods and results: MV RNA was used for microarray analysis of MVP patients versus control, highlighting genes that indicate the involvement of 5HTR pathways and extracellular matrix remodeling in MVP. These canine MVP leaflets (N=5/group) showed 5HTR2B upregulation. Conclusion: In humans, MVP is associated with an upregulation in 5HTR2B expression and increased 5HT receptor signaling in the leaflets. 5HTR signaling is involved not only in previously reported 5HTrelated valvulopathies, but it is also involved in the pathological remodeling of MVP.
2018-01-29 | GSE109744 | GEO
Project description:Mitral valve prolapse (MVP) is a common condition present in 1-3% of the population. There has been evidence that a subset of MVP patients is at higher risk of sudden cardiac death. The arrhythmogenic mechanism is related to fibrotic changes in the papillary muscles caused by the prolapsing valve. ECG features include ST-segment depression, T wave inversion or biphasic T waves in inferior leads, and premature ventricular contractions arising from the papillary muscles and the fascicular system. Echocardiography can identify MVP and mitral annular disjunction, a feature that has significant negative prognostic value in MVP. Cardiac MRI is indicated for identifying fibrosis. Patients with high-risk features should be referred for further evaluation. Catheter ablation and mitral valve repair might reduce the risk of malignant arrhythmia. MVP patients with high-risk features and clinically documented ventricular arrhythmia may also be considered for an ICD.
| S-EPMC9376835 | biostudies-literature
Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.
| S-EPMC7008556 | biostudies-literature
Project description: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.
| S-EPMC7331025 | biostudies-literature
Project description:BackgroundMitral valve thickness is used as a criterion to distinguish the classical from the non-classical form of mitral valve prolapse (MVP). Classical form of MVP has been associated with higher risk of mitral regurgitation (MR) and concomitant complications. We sought to determine the relation of mitral valve morphology and motion to mitral regurgitation severity in patients with MVP.MethodsWe prospectively analyzed transthoracic echocardiograms of 38 consecutive patients with MVP and various degrees of MR. In the parasternal long-axis view, leaflets length, diastolic leaflet thickness, prolapsing depth, billowing area and non-coaptation distance between both leaflets were measured.ResultsTwenty patients (53%) and 18 patients (47%) were identified as having moderate to severe and mild MR respectively (ERO = 45 ± 27 mm² vs. 5 ± 7 mm², p < 0.001). Diastolic leaflet thickness was similar in both groups (5.5 ± 0.9 mm vs. 5.3 ± 1 mm, p = 0.57). On multivariate analysis, the non-coaptation distance (OR 7.9 per 1 mm increase; 95% CI 1.72-37.2) was associated with significant MR. Thick mitral valve leaflet as traditionally reported (? 5 mm) was not associated with significant MR (OR 0.9; 95% CI 0.2-3.4).ConclusionsIn patients with MVP, thick mitral leaflet is not associated with significant MR. Leaflet thickness is probably not as important in risk stratification as previously reported in patients with MVP. Other anatomical and geometrical features of the mitral valve apparatus area appear to be much more closely related to MR severity.
| S-EPMC3296553 | biostudies-literature
Project description:BackgroundKnowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community using current, more specific echocardiographic criteria is unknown. In addition, the importance of nondiagnostic MVP morphologies (NDMs; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDMs increase the risk of offspring MVP.Methods and resultsStudy participants were 3679 Generation 3 individuals with available parental data in the Offspring or the New Offspring Spouse cohorts. MVP and NDMs were distinguished by leaflet displacement >2 versus ≤2 mm beyond the mitral annulus, respectively. We compared MVP prevalence in Generation 3 participants with at least 1 parent with MVP (n=186) with that in individuals without parental MVP (n=3493). Among 3679 participants (53% women; mean age, 40±9 years), 49 (1%) had MVP. Parental MVP was associated with a higher prevalence of MVP in Generation 3 participants (10 of 186, 5.4%) compared with no parental MVP (39 of 3493, 1.1%; adjusted odds ratio, 4.51; 95% confidence interval, 2.13-9.54; P<0.0001). When parental NDMs were examined alone, the prevalence of Generation 3 MVP remained higher (12 of 484, 2.5%) compared with those without parental MVP or NDMs (27 of 3009, 0.9%; adjusted odds ratio, 2.52; 95% confidence interval, 1.25-5.10; P=0.01).ConclusionsParental MVP and NDMs are associated with increased prevalence of offspring MVP, highlighting the genetic substrate of MVP and the potential clinical significance of NDMs in the community.
| S-EPMC4301989 | biostudies-literature
Project description:Mitral valve prolapse (MVP) is the most common nonischemic mitral regurgitation etiology and mitral abnormality requiring surgery in the Western world. There is an increasing awareness that pathological findings in MVP are not confined to the valve tissue; rather, it is a complex disease, involving the mitral valve apparatus, cardiac hemodynamics, and cardiac structure. Imaging has played a fundamental role in the understanding of the diagnosis, prevalence, and consequences of MVP. The diagnosis of MVP by imaging is based upon demonstrating valve leaflets ascending into the left atrium through the saddle-shaped annulus. Transthoracic and transesophageal echocardiography are the primary modalities in the diagnosis and assessment of MVP patients and must include careful assessment of the leaflets, annulus, chords, and papillary muscles. High-spatial-resolution imaging modalities such as cardiac magnetic resonance images and cardiac computed tomography play a secondary role in this regard and can demonstrate the anatomical relation between the mitral valve annulus and leaflet excursion for appropriate diagnosis. Ongoing development of new methods of cardiac imaging can help us to accurately understand the mechanism, diagnose the disease, develop an appropriate treatment plan, and estimate the risk for sudden death. Recently, several new observations with respect to prolapse have been derived from cardiac imaging including three-dimensional echocardiography and tissue-Doppler imaging. The aim of this article is to present these new imaging-derived insights for the diagnosis, risk assessment, treatment, and follow-up of patients with MVP.
| S-EPMC10236887 | biostudies-literature