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ERBB2 R599C variant is associated with left ventricular outflow tract obstruction defects in human

ABSTRACT: Non-syndromic congenital heart defects (CHD) are occasionally familial and left ventricular out flow tract obstruction (LVOTO) defects are among the subtypes with the highest hereditability. The aim of this study was to evaluate the pathogenicity of a heterozygous ERBB2 variant R599C identified in three families with LVOTO defects.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Markku Varjosalo

PROVIDER: MSV000093153 | MassIVE | Thu Oct 19 08:29:00 BST 2023

REPOSITORIES: MassIVE

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ERBB2 R599C variant is associated with left ventricular outflow tract obstruction defects in human

Project description:Non-syndromic congenital heart defects (CHD) are occasionally familial and left ventricular out flow tract obstruction (LVOTO) defects are among the subtypes with the highest hereditability. The aim of this study was to evaluate the pathogenicity of a heterozygous ERBB2 variant R599C identified in three families with LVOTO defects.

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ERBB2 R599C variant is associated with left ventricular outflow tract obstruction defects in human

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Project description:BackgroundThe left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation.MethodsWe selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry.ResultsWe identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p=0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype.ConclusionThese results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.

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NOTCH1 missense alleles associated with left ventricular outflow tract defects exhibit impaired receptor processing and defective EMT.

Project description:Notch signaling is essential for proper cardiac development. We recently identified missense variants in the NOTCH1 receptor in patients with diverse left ventricular outflow tract (LVOT) malformations (NOTCH1(G661S) and NOTCH1(A683T)) that reduce ligand-induced Notch signaling. Here, we examine the molecular mechanisms that contribute to reduced signaling and perturbed development. We find that NOTCH1(A683T) exhibits reduced S1 cleavage due to impaired trafficking through the endoplasmic reticulum (ER). This observation is consistent with improper localization of the variant receptor to the ER and decreased presentation at the cell surface. In contrast, the nearby mutation NOTCH1(G661S) exhibits reduced cell-surface presentation in the absence of overt folding or trafficking defects. To examine the implications of these variants in disease pathogenesis, we investigated their effect on epithelial-to-mesenchymal transition (EMT), a critical process for development of the outflow tract. We find that these LVOT-associated NOTCH1 alleles can contribute to defective EMT in endothelial cell lines through impaired induction of Snail and Hes family members. These data represent the first description of a molecular mechanism underlying NOTCH1 mutations in individuals with LVOT malformations, and have important implications regarding the functional contribution of these alleles to a complex set of developmental defects.

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