Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants

Familial dilated cardiomyopathy (DCM), clinically characterized by enlargement and dysfunction of one or both ventricles of the heart, can be caused by variants in sarcomeric genes including TNNC1 (encoding cardiac troponin C, cTnC). Here, we report the case of two siblings with severe, early onset...

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Main Authors: Maicon Landim-Vieira, Jamie R. Johnston, Weizhen Ji, Emily K. Mis, Joshua Tijerino, Michele Spencer-Manzon, Lauren Jeffries, E. Kevin Hall, David Panisello-Manterola, Mustafa K. Khokha, Engin Deniz, P. Bryant Chase, Saquib A. Lakhani, Jose Renato Pinto
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-01-01
Series:Frontiers in Physiology
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fphys.2019.01612/full
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author Maicon Landim-Vieira
Jamie R. Johnston
Weizhen Ji
Emily K. Mis
Joshua Tijerino
Michele Spencer-Manzon
Michele Spencer-Manzon
Lauren Jeffries
E. Kevin Hall
David Panisello-Manterola
Mustafa K. Khokha
Mustafa K. Khokha
Engin Deniz
P. Bryant Chase
Saquib A. Lakhani
Jose Renato Pinto
spellingShingle Maicon Landim-Vieira
Jamie R. Johnston
Weizhen Ji
Emily K. Mis
Joshua Tijerino
Michele Spencer-Manzon
Michele Spencer-Manzon
Lauren Jeffries
E. Kevin Hall
David Panisello-Manterola
Mustafa K. Khokha
Mustafa K. Khokha
Engin Deniz
P. Bryant Chase
Saquib A. Lakhani
Jose Renato Pinto
Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
Frontiers in Physiology
genetic analysis
cardiac troponin C
missense variant
dilated cardiomyopathy
TNNC1
author_facet Maicon Landim-Vieira
Jamie R. Johnston
Weizhen Ji
Emily K. Mis
Joshua Tijerino
Michele Spencer-Manzon
Michele Spencer-Manzon
Lauren Jeffries
E. Kevin Hall
David Panisello-Manterola
Mustafa K. Khokha
Mustafa K. Khokha
Engin Deniz
P. Bryant Chase
Saquib A. Lakhani
Jose Renato Pinto
author_sort Maicon Landim-Vieira
title Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
title_short Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
title_full Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
title_fullStr Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
title_full_unstemmed Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
title_sort familial dilated cardiomyopathy associated with a novel combination of compound heterozygous tnnc1 variants
publisher Frontiers Media S.A.
series Frontiers in Physiology
issn 1664-042X
publishDate 2020-01-01
description Familial dilated cardiomyopathy (DCM), clinically characterized by enlargement and dysfunction of one or both ventricles of the heart, can be caused by variants in sarcomeric genes including TNNC1 (encoding cardiac troponin C, cTnC). Here, we report the case of two siblings with severe, early onset DCM who were found to have compound heterozygous variants in TNNC1: p.Asp145Glu (D145E) and p.Asp132Asn (D132N), which were inherited from the parents. We began our investigation with CRISPR/Cas9 knockout of TNNC1 in Xenopus tropicalis, which resulted in a cardiac phenotype in tadpoles consistent with DCM. Despite multiple maneuvers, we were unable to rescue the tadpole hearts with either human cTnC wild-type or patient variants to investigate the cardiomyopathy phenotype in vivo. We therefore utilized porcine permeabilized cardiac muscle preparations (CMPs) reconstituted with either wild-type or patient variant forms of cTnC to examine effects of the patient variants on contractile function. Incorporation of 50% WT/50% D145E into CMPs increased Ca2+ sensitivity of isometric force, consistent with prior studies. In contrast, incorporation of 50% WT/50% D132N, which had not been previously reported, decreased Ca2+ sensitivity of isometric force. CMPs reconstituted 50–50% with both variants mirrored WT in regard to myofilament Ca2+ responsiveness. Sinusoidal stiffness (SS) (0.2% peak-to-peak) and the kinetics of tension redevelopment (kTR) at saturating Ca2+ were similar to WT for all preparations. Modeling of Ca2+-dependence of kTR support the observation from Ca2+ responsiveness of steady-state isometric force, that the effects on each mutant (50% WT/50% mutant) were greater than the combination of the two mutants (50% D132N/50% D145E). Further studies are needed to ascertain the mechanism(s) of these variants.
topic genetic analysis
cardiac troponin C
missense variant
dilated cardiomyopathy
TNNC1
url https://www.frontiersin.org/article/10.3389/fphys.2019.01612/full
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spelling doaj-d54c1495d9574db285c1dbf9401684142020-11-25T02:19:35ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-01-011010.3389/fphys.2019.01612486119Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 VariantsMaicon Landim-Vieira0Jamie R. Johnston1Weizhen Ji2Emily K. Mis3Joshua Tijerino4Michele Spencer-Manzon5Michele Spencer-Manzon6Lauren Jeffries7E. Kevin Hall8David Panisello-Manterola9Mustafa K. Khokha10Mustafa K. Khokha11Engin Deniz12P. Bryant Chase13Saquib A. Lakhani14Jose Renato Pinto15Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United StatesDepartment of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Genetics, Yale School of Medicine, Yale University, New Haven, CT, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Genetics, Yale School of Medicine, Yale University, New Haven, CT, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Biological Science, Florida State University, Tallahassee, FL, United StatesPediatric Genomics Discovery Program, Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, CT, United StatesDepartment of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United StatesFamilial dilated cardiomyopathy (DCM), clinically characterized by enlargement and dysfunction of one or both ventricles of the heart, can be caused by variants in sarcomeric genes including TNNC1 (encoding cardiac troponin C, cTnC). Here, we report the case of two siblings with severe, early onset DCM who were found to have compound heterozygous variants in TNNC1: p.Asp145Glu (D145E) and p.Asp132Asn (D132N), which were inherited from the parents. We began our investigation with CRISPR/Cas9 knockout of TNNC1 in Xenopus tropicalis, which resulted in a cardiac phenotype in tadpoles consistent with DCM. Despite multiple maneuvers, we were unable to rescue the tadpole hearts with either human cTnC wild-type or patient variants to investigate the cardiomyopathy phenotype in vivo. We therefore utilized porcine permeabilized cardiac muscle preparations (CMPs) reconstituted with either wild-type or patient variant forms of cTnC to examine effects of the patient variants on contractile function. Incorporation of 50% WT/50% D145E into CMPs increased Ca2+ sensitivity of isometric force, consistent with prior studies. In contrast, incorporation of 50% WT/50% D132N, which had not been previously reported, decreased Ca2+ sensitivity of isometric force. CMPs reconstituted 50–50% with both variants mirrored WT in regard to myofilament Ca2+ responsiveness. Sinusoidal stiffness (SS) (0.2% peak-to-peak) and the kinetics of tension redevelopment (kTR) at saturating Ca2+ were similar to WT for all preparations. Modeling of Ca2+-dependence of kTR support the observation from Ca2+ responsiveness of steady-state isometric force, that the effects on each mutant (50% WT/50% mutant) were greater than the combination of the two mutants (50% D132N/50% D145E). Further studies are needed to ascertain the mechanism(s) of these variants.https://www.frontiersin.org/article/10.3389/fphys.2019.01612/fullgenetic analysiscardiac troponin Cmissense variantdilated cardiomyopathyTNNC1