TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy

Jeanne L. Theis, Michael T. Zimmermann, Brandon Larsen, Inna N. Rybakova, Pamela A. Long, Jared M. Evans, Sumit Middha, Mariza De Andrade, Richard L. Moss, Eric D Wieben, Virginia V. Michels, Timothy Mark Olson

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes,yet the molecular basis forthese disorders remainsidiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.

Original languageEnglish (US)
Pages (from-to)5793-5804
Number of pages12
JournalHuman Molecular Genetics
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2014

Fingerprint

Dilated Cardiomyopathy
Tachycardia
Exome
Mutation
Phosphotransferases
Phenotype
Intranuclear Inclusion Bodies
Protein Deficiency
Troponin I
Genetic Association Studies
Dimerization
Missense Mutation
Computer Simulation
Atrial Fibrillation
Cardiac Arrhythmias
Heart Diseases
Chromosomes
Genome
Staining and Labeling
Peptides

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy. / Theis, Jeanne L.; Zimmermann, Michael T.; Larsen, Brandon; Rybakova, Inna N.; Long, Pamela A.; Evans, Jared M.; Middha, Sumit; De Andrade, Mariza; Moss, Richard L.; Wieben, Eric D; Michels, Virginia V.; Olson, Timothy Mark.

In: Human Molecular Genetics, Vol. 23, No. 21, 01.11.2014, p. 5793-5804.

Research output: Contribution to journalArticle

Theis, Jeanne L. ; Zimmermann, Michael T. ; Larsen, Brandon ; Rybakova, Inna N. ; Long, Pamela A. ; Evans, Jared M. ; Middha, Sumit ; De Andrade, Mariza ; Moss, Richard L. ; Wieben, Eric D ; Michels, Virginia V. ; Olson, Timothy Mark. / TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 21. pp. 5793-5804.
@article{88607c547d6645df907e9a94f076a13d,
title = "TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy",
abstract = "Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes,yet the molecular basis forthese disorders remainsidiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.",
author = "Theis, {Jeanne L.} and Zimmermann, {Michael T.} and Brandon Larsen and Rybakova, {Inna N.} and Long, {Pamela A.} and Evans, {Jared M.} and Sumit Middha and {De Andrade}, Mariza and Moss, {Richard L.} and Wieben, {Eric D} and Michels, {Virginia V.} and Olson, {Timothy Mark}",
year = "2014",
month = "11",
day = "1",
doi = "10.1093/hmg/ddu297",
language = "English (US)",
volume = "23",
pages = "5793--5804",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "21",

}

TY - JOUR

T1 - TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy

AU - Theis, Jeanne L.

AU - Zimmermann, Michael T.

AU - Larsen, Brandon

AU - Rybakova, Inna N.

AU - Long, Pamela A.

AU - Evans, Jared M.

AU - Middha, Sumit

AU - De Andrade, Mariza

AU - Moss, Richard L.

AU - Wieben, Eric D

AU - Michels, Virginia V.

AU - Olson, Timothy Mark

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes,yet the molecular basis forthese disorders remainsidiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.

AB - Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes,yet the molecular basis forthese disorders remainsidiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.

UR - http://www.scopus.com/inward/record.url?scp=84911374570&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911374570&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu297

DO - 10.1093/hmg/ddu297

M3 - Article

C2 - 24925317

AN - SCOPUS:84911374570

VL - 23

SP - 5793

EP - 5804

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 21

ER -