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 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.
authors.affiliation: Cardiovascular Genetics Research Laboratory.
authors.forename: Jeanne L
authors.initials: JL
authors.lastname: Theis
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Zimmermann
authors.affiliation: Department of Laboratory Medicine and Pathology.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Larsen
authors.affiliation: Department of Cell and Regenerative Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Inna N
authors.initials: IN
authors.lastname: Rybakova
authors.affiliation: Cardiovascular Genetics Research Laboratory.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Long
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Evans
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research.
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Department of Cell and Regenerative Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.affiliation: Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA and.
authors.forename: Virginia V
authors.initials: VV
authors.lastname: Michels
authors.affiliation: Cardiovascular Genetics Research Laboratory, Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, olson.timothy@mayo.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D017124:Conserved Sequence; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D014644:Genetic Variation; D006239:Haplotypes; D006329:Heart Conduction System / Q000002:abnormalities*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009930:Organic Chemicals; D010375:Pedigree; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases; D016415:Sequence Alignment; D013577:Syndrome; D013612:Tachycardia, Ectopic Atrial / Q000175:diagnosis / Q000235:genetics*
chemical_list: D009930:Organic Chemicals; C431805:Phen Green SK; D017346:Protein Serine-Threonine Kinases; C481078:TNNI3K protein, human; D020930:MAP Kinase Kinase Kinases