KBTBD13 is a novel cardiomyopathy gene

Abstract

KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

Keywords: KBTBD13; NEM6; cardiomyopathy; congenital myopathy.

Figure 1

Pedigree Family 1. Partly or fully filled symbols represent affected individuals (see box for explanation); open symbols: unaffected individuals; diagonal line: deceased; arrow: proband; circle: female; square: male; the number in the symbols indicate the number of individuals (if >1). CMP, cardiomyopathy; LVEF, left ventricular ejection fraction; NEM, nemaline myopathy.

Figure 2

Characterization of Kbtbd13^R408C‐knockin and Kbtbd13‐knockout mice. (a) qPCR with primers that detect both WT and mutant Kbtbd13 transcript show comparable mRNA levels in Kbtbd13 ^R408C ‐WT (WT) and homozygous Kbtbd13 ^R408C ‐KI (KI) mice. Kbtbd13 transcript was normalized to housekeeping gene Csnk2a2. (b) (left) Whole heart mass and (right) left ventricle wall thickness were comparable between Kbtbd13 ^R408C ‐KI (KI) mice and Kbtbd13 ^R408C ‐WT (WT) mice. (c) (upper panel) Histological evaluation by Hematoxylin‐eosin, (middle panel) Picrosirius, and (lower panel) Gomori‐trichrome stainings showed normal structure of the left ventricle, no fibrosis and no protein aggregates in the cardiomyocytes of KI mice (scale bar = 50 µm). (d) Stress echocardiography revealed no changes left ventricle ejection fraction (LVEF) in KI mice, both at rest and upon dobutamine administration. (e) (left) Pressure‐volume relations showed an unaffected end‐systolic pressure‐volume relation (ESPVR), (right) whereas the end‐diastolic pressure‐volume relation (EDPVR) was significantly steeper in KI mice compared with WT mice. (f) qPCR with Kbtbd13 primers show no detectable mRNA levels in KO mice. Kbtbd13 transcript was normalized to housekeeping gene Csnk2a2. (g) (left) Whole heart mass and (right) left ventricular wall thickness were lower in KO mice compared with WT mice. (h) (upper panel) Histological evaluation by Hematoxylin‐eosin, (middle panel) Picrosirius, and (lower panel) Gomori‐trichrome stainings showed normal structure of the left ventricle, no fibrosis and no protein aggregates in the cardiomyocytes of KO mice (scale bar = 50 µm). (i) Stress echocardiography revealed no changes in LVEF at baseline. However, upon dobutamine administration, KO mice had a blunted increase in LVEF (P‐interaction < 0.01). (j) (left) Pressure‐volume relations revealed a lower ESPVR in KO mice, and (right) no changes in the EDPVR compared with WT mice.