Mutations inNTRK3Suggest a Novel Signaling Pathway in Human Congenital Heart Disease


    loading  Checking for direct PDF access through Ovid

Abstract

Congenital heart defects (CHDs) are the most common major birth defects and the leading cause of death from congenital malformations. The etiology remains largely unknown, though genetic variants clearly contribute. In a previous study, we identified a large copy-number variant (CNV) that deleted 46 genes in a patient with a malalignment type ventricular septal defect (VSD). The CNV included the geneNTRK3encoding neurotrophic tyrosine kinase receptor C (TrkC), which is essential for normal cardiogenesis in animal models. To evaluate the role ofNTRK3in human CHDs, we studied 467 patients with related heart defects forNTRK3mutations. We identified four missense mutations in four patients with VSDs that were not found in ethnically matched controls and were predicted to be functionally deleterious. Functional analysis using neuroblastoma cell lines expressing mutant TrkC demonstrated that one of the mutations (c.278C>T, p.T93M) significantly reduced autophosphorylation of TrkC in response to ligand binding, subsequently decreasing phosphorylation of downstream target proteins. In addition, compared with wild type, three of the four cell lines expressing mutant TrkC showed altered cell growth in low-serum conditions without supplemental neurotrophin 3. These findings suggest a novel pathophysiological mechanism involvingNTRK3in the development of VSDs.Congenital heart defects (CHD) are the most common major birth defects. We identified four missense mutations in NTRK3 (TrkC) in patients with a ventricular septal defect. One of the mutations significantly reduced autophosphorylation of TrkC subsequently decreasing phosphorylation of downstream target proteins. In addition, three cell lines expressing different mutant TrkC showed altered cell growth compared to wildtype TrkC. These findings implicate a novel candidate signaling pathway, the disruption of which may contribute to human CHD.

    loading  Loading Related Articles