Congenital heart disease (CHD) is one of the most common birth defects. Studies in animal models and humans have indicated a genetic etiology for CHD. About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important for heart development. Recent studies have shown genes encoding chromatin modifiers, cilia related proteins, and cilia-transduced cell signaling pathways play important roles in CHD pathogenesis. Elucidating the genetic etiology of CHD will help improve diagnosis and the development of new therapies to improve patient outcomes.

https://www.mdpi.com/2218-273X/9/12/879/pdf

Genetics of Congenital Heart Disease

New explanation for autosomal dominant high bone mass: Mutation of low-density lipoprotein receptor-related protein 6.

Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.

Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants.

Gastrulation and neurulation are successive morphogenetic processes that play key roles in shaping the basic embryonic body plan. Importantly, they operate through common cellular and molecular mechanisms to set up the three spatially organized germ layers and to close the neural tube. During gastrulation and neurulation, convergent extension movements driven by cell intercalation and oriented cell division generate major forces to narrow the germ layers along the mediolateral axis and elongate the embryo in the anteroposterior direction. Apical constriction also makes an important contribution to promote the formation of the blastopore and the bending of the neural plate. Planar cell polarity proteins are major regulators of asymmetric cell behaviors and critically involved in a wide variety of developmental processes, from gastrulation and neurulation to organogenesis. Mutations of planar cell polarity genes can lead to general defects in the morphogenesis of different organs and the co-existence of distinct congenital diseases, such as spina bifida, hearing deficits, kidney diseases, and limb elongation defects. This review outlines our current understanding of non-canonical Wnt signaling, commonly known as Wnt/planar cell polarity signaling, in regulating morphogenetic movements of gastrulation and neural tube closure during development and disease. It also attempts to identify unanswered questions that deserve further investigations. 

/pdf/wnt-planar-cell-polarity-signaling-controls-morphogenetic-3a1nde77.pdf

Wnt/planar cell polarity signaling controls morphogenetic movements of gastrulation and neural tube closure

The role of ligand endocytosis in notch signalling.

Background
Neural tube defects (NTDs), the second most frequent cause of human congenital abnormalities, are debilitating birth defects due to failure of neural tube closure It has been shown that noncanonical WNT/planar cell polarity (PCP) signaling is required for convergent extension (CE), the initiation step of neural tube closure (NTC) But the effect of canonical WNT//β-catenin signaling during NTC is still elusive LRP6 (low density lipoprotein receptor related proteins 6) was identified as a co-receptor for WNT/β-catenin signaling, but recent studies showed that it also can mediate WNT/PCP signaling

Methods
In this study, we screened mutations in the LRP6 gene in 343 NTDs and 215 ethnically matched normal controls of Chinese Han population

Results
Three rare missense mutations (c1514A>G, pY505C); c2984A>G, pD995G; and c4280C>A, pP1427Q) of the LRP6 gene were identified in Chinese NTD patients The Y505C mutation is a loss-of-function mutation on both WNT/β-catenin and PCP signaling The D995G mutation only partially lost inhibition on PCP signaling without affecting WNT/β-catenin signaling The P1427Q mutation dramatically increased WNT/β-catenin signaling but only mildly loss of inhibition on PCP signaling All three mutations failed to rescue CE defects caused by lrp6 morpholino oligos knockdown in zebrafish Of interest, when overexpressed, D995G did not induce any defects, but Y505C and P1427Q caused more severe CE defects in zebrafish

Conclusion
Our results suggested that over-active canonical WNT signaling induced by gain-of-function mutation in LRP6 could also contribute to human NTDs, and a balanced WNT/β-catenin and PCP signaling is probably required for proper neural tube development Birth Defects Research 110:63–71, 2018 © 2017 Wiley Periodicals, Inc

Novel Mutation of LRP6 Identified in Chinese Han Population Links Canonical WNT Signaling to Neural Tube Defects

Coordinated migration of the mesoderm is essential for accurate organization of the body plan during embryogenesis. However, little is known about how mesoderm migration influences posterior neural tube closure in mammals. Here we show that spinal neural tube closure and lateral migration of the caudal paraxial mesoderm depend on Transmembrane protein 132A (TMEM132A), a single-pass type I transmembrane protein, the function of which is not fully understood. Our study in Tmem132a-null mice and cell models demonstrates that TMEM132A regulates several integrins and downstream integrin pathway activation as well as cell migration behaviors. Our data also implicates mesoderm migration in elevation of the caudal neural folds and successful closure of the caudal neural tube. These results suggest a requirement for paraxial mesodermal cell migration during spinal neural tube closure, disruption of which may lead to spinal bifida.

TMEM132A ensures mouse caudal neural tube closure and regulates integrin-based mesodermal migration.

The Glioma-associated oncogene (Gli) family members of zinc finger DNA-binding proteins are core effectors of Sonic hedgehog (SHH) signaling pathway. Studies in model organisms have identified that the Gli genes play critical roles during organ development, including the heart, brain, kidneys, etc. Deleterious mutations in GLI genes have previously been revealed in several human developmental disorders, but few in congenital heart disease (CHD). In this study, the mutations in GLI1-3 genes were captured by next generation sequencing in human cohorts composed of 412 individuals with CHD and 213 ethnically matched normal controls. A total of 20 patient-specific nonsynonymous rare mutations in coding regions of human GLI1-3 genes were identified. Functional analyses showed that GLI1 c.820G> T (p.G274C) is a gain-of-function mutation, while GLI1 c.878G>A (p.R293H) and c.1442T>A (p.L481X) are loss-of-function mutations. Our findings suggested that deleterious rare mutations in GLI1 gene broke the balance of the SHH signaling pathway regulation and may constitute a great contribution to human CHD, which shed new light on understanding genetic mechanism of embryo cardiogenesis regulated by SHH signaling.

/pdf/deleterious-rare-mutations-of-gli1-dysregulate-sonic-tq13olcr.pdf

Deleterious Rare Mutations of GLI1 Dysregulate Sonic Hedgehog Signaling in Human Congenital Heart Disease

Congenital heart defects (CHDs) are one of the most common human birth defects worldwide. TBX20 is a crucial transcription factor for the development of embryonic cardiovascular system. Previous studies have demonstrated that mutations in the TBX20 coding region contribute to familial and sporadic CHD occurrence. However, it remains largely unknown whether variants in the TBX20 regulatory region are also related to CHDs. In this study, we sequenced the 2 kb region upstream of the TBX20 transcription start site in 228 CHD patients and 292 controls in a Han Chinese population. Among the 8 single nucleotide polymorphisms (SNPs) identified, six SNPs are in strong linkage disequilibrium and the minor alleles are associated with lower CHD risk (for rs10235849 chosen as tag SNP, p = 0.0069, OR (95% CI) = 0.68 (0.51–0.90)). Functional analysis showed that the minor alleles have lower transcriptional activity than major alleles in both human heart tissues and three cell lines. The electrophoretic mobility shift assay suggested that TBX20 minor alleles may exhibit higher binding affinity with certain transcription repressors. Our results indicate that a moderately lower TBX20 activity potentially reduces CHD risk in the Han Chinese population, providing new insight in the study of CHD etiology.

/pdf/mild-decrease-in-tbx20-promoter-activity-is-a-potentially-865jgs3t2p.pdf

Mild decrease in TBX20 promoter activity is a potentially protective factor against congenital heart defects in the Han Chinese population.

Congenital heart disease (CHD) is one of the most common birth defects in humans, but its genetic etiology remains largely unknown despite decades of research. The Notch signaling pathway plays critical roles in embryonic cardiogenesis. Mind bomb 1 (Mib1) is a vital protein that activates the Notch signaling pathway through promoting ubiquitination, endocytosis and subsequent activation of Notch ligands. Previous studies show that Mib1 knockout in mice completely abolishes Notch signaling, leading to cardiac deformity. However, the function of MIB1 and its potential disease-causing mutations are poorly studied in human CHD. In this research, we identified four novel non-synonymous heterozygous rare mutations of MIB1 from 417 Han Chinese CHD patients. The following biochemical analyses revealed that mutations p.T312K fs*55 and p.W271G significantly deplete MIB1’s function, resulting in a lower level of JAGGED1 (JAG1) ubiquitination and Notch signaling induction. Our results suggest that pathologic variants in MIB1 may contribute to CHD occurrence, shedding new light on the genetic mechanism of CHD in the context of the Notch signaling pathway.

/pdf/mib1-mutations-reduce-notch-signaling-activation-and-1zfcfr8wuk.pdf

MIB1 mutations reduce Notch signaling activation and contribute to congenital heart disease.

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