. Author manuscript; available in PMC: 2019 Aug 1.

Published in final edited form as: Pediatr Cardiol. 2018 May 15;39(6):1099–1106. doi: 10.1007/s00246-018-1882-z

Table 1.

Summary of mouse models for LVNC

Mouse model	Gene function and mutant mouse phenotype

Fkbp1a Loss-of-function [43]	Play a role in immunoregulation and basic cellular processes involving protein folding and trafficking.
Fkbp1a Loss-of-function [43]	Fkbp1a-deficient mice have severe dilated cardiomyopathy, ventricular septal defects and LVNC.

Jarid2 (Jumonji) Loss-of-function [44]	Nuclear protein and transcriptional regulator, and necessary for mouse embryogenesis.
Jarid2 (Jumonji) Loss-of-function [44]	The jmj homozygous mouse embryos showed heart malformations, including the ventriclar septal defect, noncompaction of the ventricular wall, double-outlet right ventricle, and dilated atria.

PBP/TRAP220 Loss-of-function [45]	Functions as a nuclear receptor coactivator, working with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus.
PBP/TRAP220 Loss-of-function [45]	PBP null mutation mice have noncompaction of the ventricular myocardium and resultant dilatation and cause embryonic lethality at E11.5.

Pegl(Mest) Loss-of-function [46]	Mesoderm specific, encodes a member of the alpha/beta hydrolase superfamily, has isoform-specific imprinting, and plays a role in development.
Pegl(Mest) Loss-of-function [46]	Peg1 knock out mice have a subtle alteration in the pattern of trabeculation: an increase in thickness and reduction in density of the compact myocardium.

TACE (ADAM17) Loss-of-function [47]	Member of a family of transmembrane and secreted metalloendopeptidases. Involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis.
TACE (ADAM17) Loss-of-function [47]	TACE null mutation die at birth, phenotypes include the failure of eyelid fusion, hair and skin defects, abnormalities of lung development, markedly enlarged fetal hearts with increased myocardial trabeculation and reduced compaction at late gestation.

Scrib/Vangl2 Loss-of-function [48]	Both involved in PCP signaling and was shown to be involved in synaptic function, neuroblast differentiation, and epithelial polarization.
Scrib/Vangl2 Loss-of-function [48]	Crc mice (Scrib mutant) develop heart malformations, cardiac misalignment defects and ventricular noncompaction. Double heterozygosity of both Scrib and Vangl2 can cause cardiac defects similar to those found in homozygous mutants for each gene but without other major defects.

Vangl2 Loss-of-function [49]	A membrane protein involved in the regulation of planar cell polarity, especially in the stereociliary bundles of the cochlea.
Vangl2 Loss-of-function [49]	Lp mice (Vangl2 mutant) develop double outlet right ventricle with perimembranous ventricular septal defects and aortic arch defects, and the defects are caused by mutations in the Vangl2 gene, mutant ventricles have characteristics of noncompaction.

PTPN11(SHP2) Q79R Gain-of-function mutation [50]	Regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation.
PTPN11(SHP2) Q79R Gain-of-function mutation [50]	SHP2 (Q79R) transgenic mice selectively activated the ERK 1/2 pathway and cause aberrant cardiac architecture during cardiac development, including ventricular noncompaction.

FRNK Gain-of-function mutation [51]	Cytoplasmic protein tyrosine kinase found in the focal adhesions that form between cells growing in the presence of extracellular matrix.
FRNK Gain-of-function mutation [51]	Cardiac-specific over-expression of FRNK 5 lead to a severe ventricular noncompaction defect associated with reduced cardiomyocyte proliferation.

cTNT(E96K) Gain-of-function mutation [37]	The protein located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. cTNT (E96K) is linked to LVNC.
cTNT(E96K) Gain-of-function mutation [37]	cTNT mutant mice displayed an impaired left ventricular function and induction of marker genes of heart failure. Left ventricular non-compaction was not observed.

Gbe1(E609X) Loss-of-function [52]	Encodes a glycogen branching enzyme that adds short glucosyl chains in α-1,6 glycosidic links to the glycogen molecule to yield a branched polymer with increased water solubility and glycogen synthetic activity.
Gbe1(E609X) Loss-of-function [52]	The ENU-induced Gbe1 mutant mice exhibit abnormal cardiac development, including hypertrabeculation and noncompaction of the ventricular wall. Poor ventricular function in late gestation and ultimately cause heart failure, fetal hydrops and embryonic lethality.

Daaml Loss-of-function [42]	A potential non-canonical Wnt/PCP signaling effector, involved in cell polarity and actin polarization.
Daaml Loss-of-function [42]	Daam1-deficient mice exhibit embryonic and neonatal lethality and suffer multiple cardiac defects, including ventricular noncompaction, double outlet right ventricles and ventricular septal defects.

YWHAE Loss-of-function [53]	Ywhae belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins, also called 14-3-3ε
YWHAE Loss-of-function [53]	Ywhae-deletion led to ventricular non-compaction and selective reduction in compact myocardium thickness.

Tafazzin (TAZ) Loss-of-function [35]	Located in mitochondria, involved in altering a fat (lipid) called cardiolipin, which plays critical roles in the mitochondrial inner membrane.
Tafazzin (TAZ) Loss-of-function [35]	TAZ knockdown (TAZKD) mice died within the neonatal period, mutant hearts show myocardial thinning, hypertrabeculation and noncompaction, and defective ventricular septation.

Mib1 Loss-of-function [36]	Encodes protein functions as an E3 ubiquitin ligase, positively regulates Notch signaling by ubiquitinating the Notch receptors, thereby facilitating their endocytosis.
Mib1 Loss-of-function [36]	Targeted inactivation of Mib1 in mouse myocardium causes LVNC, reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes.

Nkx2-5(R52G) DNA binding domain missense mutation [54]	Plays critical roles in regulating cardiac-specific gene expression essential for cardiomyocyte differentiation and heart development.
Nkx2-5(R52G) DNA binding domain missense mutation [54]	Nkx2-5^+/R52G and cardiomyocyte conditional knockout mice demonstrated noncompaction and hypertrabeculation, along with diverse cardiac anomalies, including atrioventricular septal defects, Ebstein malformation of the tricuspid valve, perimembranous and muscular ventricular septal defects, and cardiac conduction system defects.

Braf^Q241R Gain-of-function [55]	Plays important role in signaling pathway known as the RAS/MAPK pathway and its mediated cellular function.
Braf^Q241R Gain-of-function [55]	Braf^Q241R/+ mice manifested embryonic/neonatal lethality, showing liver necrosis, edema, craniofacial abnormalities, and multiple heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction and ventricular septal defects.

Caszl Loss-of-function [56]	Encodes a zinc finger transcription factor, function as a tumor suppressor, and single nucleotide polymorphisms in this gene are associated with blood pressure variation.
Caszl Loss-of-function [56]	Casz1 deletion in mice resulted in abnormal heart development including hypoplasia of myocardium, cardiac noncompaction, ventricular septal defect, and disorganized morphology.

SLC25A5/ANT2 Loss-of-function [57]	Functions as a major component in the mitochondrial permeability-transition pore complex that promotes the exchange of mitochondrial ATP with cytosolic ADP.
SLC25A5/ANT2 Loss-of-function [57]	Ant2-null embryos showed E14.5 lethality with cardiac developmental failure, immature cardiomyocytes, cardiomyocyte hyperliferation, and cardiac failure due to hypertrabeculation/noncompaction.

S1pr1 Loss-of-function [58]	Structurally similar to G protein-coupled receptors and is highly expressed in endothelial cells. It has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation.
S1pr1 Loss-of-function [58]	S1pr1 conditional knockout showed ventricular noncompaction and ventricular septal defects and perinatal lethality in majority of mutants.

NUMB/NUMBL Loss-of-function [59]	Plays a role in the determination of cell fates during development. Its primary function in cell differentiation is as an inhibitor of Notch signaling which is essential for maintaining self-renewal potential in stem and progenitor cells.
NUMB/NUMBL Loss-of-function [59]	Loss of NUMB or both NUMB and NUMBL in cardiomyocytes results in ventricular noncompaction phenotypes.

Rlf Loss-of-function [60]	Encodes a Zinc finger protein, acts as an epigenetic modifier maintaining low levels of DNA methylation at CpG island and enhancers across the genome.
Rlf Loss-of-function [60]	Two independent Rlf ENU mutant lines showed heart defects resembling LVNC at E11.5–E 14.5.

Lrp2 Loss-of-function [61]	Critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones.
Lrp2 Loss-of-function [61]	Lrp2 knockout mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium.

Slc39a8 Loss-of-function [62]	Encodes a transmembrane protein that acts as a transporter of several divalent cations, including manganese (Mn), zinc (Zn), cadmium (Cd), and iron (Fe).
Slc39a8 Loss-of-function [62]	Slc39a8-null mouse embryos do not survive embryogenesis and exhibit a LVNC phenotype.

Dtna^N49S Gain-of-function [63]	Dystrobrevin alpha belongs to the dystrobrevin subfamily and the dystrophin family. This protein is a component of the dystrophin-associated protein complex (DPC).
Dtna^N49S Gain-of-function [63]	Multiple trabeculation and a higher ratio of noncompacted to compacted myocardial layer were found in the Myh6-Dtna^N49S transgenic mice, and with left ventricular dilation and systolic dysfunction.

SRC-1 and -3 Loss-of-function [64]	Encode steroid receptor coactivator-1 (SRC-1) and SRC-3, transcriptional coactivators for nuclear hormone receptors and certain other transcription factors that regulate many genes in development and organ function.
SRC-1 and -3 Loss-of-function [64]	Ablation of SRC-1/3 in the myocardial lineage resulted in prominent trabeculae, deep intertabecular recesses and thin ventricular wall and septum.