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Mutations in NTRK3 Suggest a Novel Signaling Pathway in Human Congenital Heart Disease
Author(s) -
Werner Petra,
Paluru Prasuna,
Simpson Anisha M.,
Latney Brande,
Iyer Radhika,
Brodeur Garrett M.,
Goldmuntz Elizabeth
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22688
Subject(s) - biology , autophosphorylation , tropomyosin receptor kinase c , missense mutation , genetics , receptor tyrosine kinase , mutation , mutant , signal transduction , cancer research , medicine , microbiology and biotechnology , gene , phosphorylation , receptor , platelet derived growth factor receptor , protein kinase a , growth factor
Congenital heart defects ( CHD s) 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 gene NTRK3 encoding neurotrophic tyrosine kinase receptor C ( T rk C ), which is essential for normal cardiogenesis in animal models. To evaluate the role of NTRK3 in human CHD s, we studied 467 patients with related heart defects for NTRK3 mutations. We identified four missense mutations in four patients with VSD s that were not found in ethnically matched controls and were predicted to be functionally deleterious. Functional analysis using neuroblastoma cell lines expressing mutant T rk C demonstrated that one of the mutations (c.278 C > T , p. T 93 M ) significantly reduced autophosphorylation of T rk C 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 T rk C showed altered cell growth in low‐serum conditions without supplemental neurotrophin 3. These findings suggest a novel pathophysiological mechanism involving NTRK3 in the development of VSD s.