TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy. Hum Mol Genet 2014 Nov 01;23(21):5793-804
Date
06/14/2014Pubmed ID
24925317Pubmed Central ID
PMC4189907DOI
10.1093/hmg/ddu297Scopus ID
2-s2.0-84911374570 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes, yet the molecular basis for these disorders remains idiopathic 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 List
Theis JL, Zimmermann MT, Larsen BT, Rybakova IN, Long PA, Evans JM, Middha S, de Andrade M, Moss RL, Wieben ED, Michels VV, Olson TMAuthor
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAmino Acid Sequence
Arrhythmias, Cardiac
Brugada Syndrome
Cardiac Conduction System Disease
Cardiomyopathy, Dilated
Child
Chromosome Mapping
Chromosomes, Human, Pair 1
Conserved Sequence
Exome
Female
Genetic Association Studies
Genetic Loci
Genetic Variation
Haplotypes
Heart Conduction System
High-Throughput Nucleotide Sequencing
Humans
MAP Kinase Kinase Kinases
Male
Middle Aged
Models, Molecular
Molecular Sequence Data
Mutation
Myocardium
Organic Chemicals
Pedigree
Protein Conformation
Protein Interaction Domains and Motifs
Sequence Alignment
Syndrome
Tachycardia, Ectopic Atrial
