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

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 (WES) data from multiple members from five families with LVNC. In four out of five 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 seven 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, likely 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 WES with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

“…In B6J-Sod2 -/-mice, the presence of a normal NNT allele preserves cardiac function, delays the onset of heart failure, and extends survival to the end of gestation (24). In comparison, the suppression of NNT in zebrafish results in ventricular malformations and contractile dysfunctions (34). Moreover, in humans, relationships between decreased NNT activity, modified mitochondrial redox regulation and cardiac failure have been reported.…”

“…This contributes to a decline in bioenergetic capacity, redox regulation and antioxidant defense, exacerbating oxidative damage to cellular proteins (26). A recent report of a heterozygous frameshift mutation of NNT in humans with left ventricular noncompaction supports the assumption that NNT plays a major role in myocardium (34). However, Nickel et al (35) demonstrated a completely opposing view.…”

MIB2variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy

“…Several genes have been linked to LVNC and they encode proteins involved in cellular energy, muscle development, ion channel formation, or components of the muscle filaments [32][33][34] .…”

Malformations of the Left Ventricle

“…In the paper by Bainbridge et al, 6 whole exome sequencing from 5 families with LVNC provided causative mutations in sarcomere genes in 4/5. Subsequent sequencing of MYH7 in a larger LVNC cohort identified mutations in 18%, confirming MYH7 mutations as the single most common cause of LVNC.…”