Pulse lineResearch With Heart Logo

Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction.

TitleLoss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction.
Publication TypeJournal Article
Year of Publication2015
AuthorsBainbridge MN, Davis EE, Choi W-Y, Dickson A, Martinez HR, Wang M, Dinh H, Muzny DM, Pignatelli R, Katsanis N, Boerwinkle E, Gibbs RA
Secondary AuthorsJefferies JL
JournalCirc Cardiovasc Genet
Volume8
Issue4
Pagination544-52
Date Published2015 Aug
ISSN1942-3268
KeywordsAnimals, Animals, Genetically Modified, Embryo, Nonmammalian, Exome, Family Health, Female, Frameshift Mutation, Genetic Complementation Test, Genetic Predisposition to Disease, Humans, Isolated Noncompaction of the Ventricular Myocardium, Luminescent Proteins, Male, Microscopy, Confocal, Mitochondrial Proteins, NADP Transhydrogenase, AB-Specific, Pedigree, Sequence Analysis, DNA, Zebrafish
Abstract

BACKGROUND: Left ventricular noncompaction (LVNC) is an autosomal-dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co-occur with cardiac hypertrophy.

METHODS AND RESULTS: Here, we generated whole exome sequence data from multiple members from 5 families with LVNC. In 4 of 5 families, the candidate causative mutation segregates with disease in known LVNC genes MYH7 and TPM1. Subsequent sequencing of MYH7 in a larger LVNC cohort identified 7 novel likely disease causing variants. In the fifth family, we identified a frameshift mutation in NNT, a nuclear-encoded mitochondrial protein, not implicated previously in human cardiomyopathies. Resequencing of NNT in additional LVNC families identified a second likely pathogenic missense allele. Suppression of nnt in zebrafish caused early ventricular malformation and contractility defects, probably driven by altered cardiomyocyte proliferation. In vivo complementation studies showed that mutant human NNT failed to rescue nnt morpholino-induced heart dysfunction, indicating a probable haploinsufficiency mechanism.

CONCLUSIONS: Together, our data expand the genetic spectrum of LVNC and demonstrate how the intersection of whole exome sequence with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.

DOI10.1161/CIRCGENETICS.115.001026
Alternate JournalCirc Cardiovasc Genet
PubMed ID26025024
PubMed Central IDPMC4545476
Grant ListU54 HG003273 / HG / NHGRI NIH HHS / United States
5 U54 HG003273 / HG / NHGRI NIH HHS / United States