PUBLICATION

A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance

Authors

Huttner, I.G., Wang, L.W., Santiago, C.F., Horvat, C., Johnson, R., Cheng, D., von Frieling-Salewsky, M., Hillcoat, K., Bemand, T.J., Trivedi, G., Braet, F., Hesselson, D., Alford, K., Hayward, C.S., Seidman, J.G., Seidman, C.E., Feneley, M.P., Linke, W.A., Fatkin, D.

ID

ZDB-PUB-181026-11

Date

2018

Source

Circulation. Genomic and precision medicine 11: e002135 (Journal)

Registered Authors

Fatkin, Diane, Hesselson, Daniel, Trivedi, Gunjan

Keywords

cardiomyopathies, echocardiography, genetics, hemodynamic, titin, zebrafish

MeSH Terms

Young Adult
Hemodynamics/genetics*
Animals
Humans
Adaptation, Biological/genetics
Cardiomyopathy, Dilated/genetics*
Cardiomyopathy, Dilated/pathology
Cardiomyopathy, Dilated/physiopathology
Stroke Volume/genetics
Sarcomeres/pathology
Male
Pedigree
Genetic Association Studies
Heart/embryology
Heart/growth & development
Stress, Physiological/genetics*
Adult
Embryo, Nonmammalian
Middle Aged
Female
Animals, Genetically Modified
Zebrafish
Aged
Heart Defects, Congenital/genetics
Heart Defects, Congenital/pathology
Connectin/genetics*
Adolescent
Sequence Deletion

(all 28)

PubMed

30354343 Full text @ Circ Genom Precis Med

Abstract

Background Truncating variants in the TTN gene ( TTNtv) are common in patients with dilated cardiomyopathy (DCM) but also occur in the general population. Whether TTNtv are sufficient to cause DCM or require a second hit for DCM manifestation is an important clinical issue. Methods We generated a zebrafish model of an A-band TTNtv identified in 2 human DCM families in which early-onset disease appeared to be precipitated by ventricular volume overload. Cardiac phenotypes were serially assessed from 0 to 12 months using video microscopy, high-frequency echocardiography, and histopathologic analysis. The effects of sustained hemodynamic stress resulting from an anemia-induced hyperdynamic state were also evaluated. Results Homozygous ttna mutants had severe cardiac dysmorphogenesis and premature death, whereas heterozygous mutants ( ttna^tv/+) survived into adulthood and spontaneously developed DCM. Six-month-old ttna^tv/+ fish had reduced baseline ventricular systolic function and failed to mount a hypercontractile response when challenged by hemodynamic stress. Pulsed wave and tissue Doppler analysis also revealed unsuspected ventricular diastolic dysfunction in ttna^tv/+ fish with prolonged isovolumic relaxation and increased diastolic passive stiffness in the absence of myocardial fibrosis. These defects reduced diastolic reserve under stress conditions and resulted in disproportionately greater atrial dilation than observed in wild-type fish. Conclusions Heterozygosity for A-band titin truncation is sufficient to cause DCM in adult zebrafish. Abnormalities of systolic and diastolic reserve in titin-truncated fish reduce stress tolerance and may contribute to a substrate for atrial arrhythmogenesis. These data suggest that hemodynamic stress may be an important modifiable risk factor in human TTNtv-related DCM.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
nppa	ttn.2^vcc14/+	control	Adult	heart	RTPCR	Fig. 5
nppa	ttn.2^vcc14/+	chemical treatment by environment: phenylhydrazine	Adult	heart	RTPCR	Fig. 5
nppa	WT	control	Adult	heart	RTPCR	Fig. 5
nppa	WT	chemical treatment by environment: phenylhydrazine	Adult	heart	RTPCR	Fig. 5
nppb	ttn.2^vcc14/+	control	Adult	heart	RTPCR	Fig. 5
nppb	ttn.2^vcc14/+	chemical treatment by environment: phenylhydrazine	Adult	heart	RTPCR	Fig. 5
nppb	WT	chemical treatment by environment: phenylhydrazine	Adult	heart	RTPCR	Fig. 5
nppb	WT	control	Adult	heart	RTPCR	Fig. 5

1 - 8 of 8

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: phenylhydrazine	Adult	atrium increased area, abnormal	Fig. 5
WT	chemical treatment by environment: phenylhydrazine	Adult	blood hemoglobin decreased amount, abnormal	Fig. 5
WT	chemical treatment by environment: phenylhydrazine	Adult	cardiac ventricle heart contraction increased occurrence, abnormal	Fig. 5
WT	chemical treatment by environment: phenylhydrazine	Adult	cardiac ventricle increased size, abnormal	Fig. 5
WT	chemical treatment by environment: phenylhydrazine	Adult	heart nppb expression increased amount, abnormal	Fig. 5
ttn.2^vcc14/+	control	Adult	cardiac ventricle heart contraction decreased occurrence, abnormal	Fig. 5
ttn.2^vcc14/+	control	Adult	heart nppa expression decreased amount, abnormal	Fig. 5
ttn.2^vcc14/+	standard conditions	Prim-5	blood circulation occurrence, normal	Fig. 2
ttn.2^vcc14/+	standard conditions	Prim-5	heart morphology, normal	Fig. 2
ttn.2^vcc14/+	standard conditions	Long-pec	atrium heart contraction process quality, normal	Fig. 2

1 - 10 of 65

Show

Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
vcc14		Small Deletion	ttn.2

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
dilated cardiomyopathy	ttn.2^vcc14/+	standard conditions	TAS
dilated cardiomyopathy	ttn.2^vcc14/+	chemical treatment by environment: phenylhydrazine	TAS

1 - 2 of 2

Show

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ttn.2	TALEN3-ttn.2	TALEN

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Huttner et al., 2018 ZDB-PUB-181026-11 PMID:30354343

A-Band Titin Truncation in Zebrafish Causes Dilated Cardiomyopathy and Hemodynamic Stress Intolerance

Huttner et al., 2018

ZDB-PUB-181026-11
PMID:30354343