O.13Nemaline myopathy patients with mutations in KBTBD13 display a cardiac phenotype

Abstract

Nemaline myopathy due to mutations in KBTBD13 (NEM6) is characterized by mild proximal weakness and a peculiar slowness of muscle relaxation. KBTBD13 is also expressed in cardiac muscle. However, a cardiac phenotype in NEM6 has not been reported yet. A member of a large family with the NEM6 Dutch founder mutation KBTBD13R408C visited our cardiogenetic outpatient clinic because of dilated cardiomyopathy. Hence, we aimed to elucidate the consequences of KBTBD13-mutations on cardiac function. A pedigree was constructed, medical reports on cardiac characteristics were collected and cardiological evaluation (ECG, echocardiography, ultrasound and MRI on indication) was performed. We engineered a Kbtbd13-knockout mouse model and performed echocardiography at rest and during acute stress (i.e. administration of dobutamine) in nine month old mice. Forty-two NEM6 patients harboring the Dutch founder mutation KBTBD13R408C underwent cardiological evaluation. Thirty-seven patients (88%) displayed a cardiac phenotype: eighteen patients revealed (mild) left ventricular dysfunction and twenty-one patients showed rhythm disorders. Recently, two patients with rhythm disorders received an implantable cardioverter-defibrillator (ICD). Pedigree analysis revealed four cases of sudden cardiac death. Functional evaluation by echocardiography revealed that upon dobutamine administration Kbtbd13-knockout mice had a blunted increase in heart rate (P-interaction < 0.01) and fractional shortening (P-interaction < 0.05). No changes in diastolic parameters (i.e. E/A ratio, E/E' ratio) were observed. Thus Kbtbd13-deficiency causes an impaired response upon acute cardiac stress. On the basis of these findings, we recommend cardiological evaluation of families with a mutation in KBTBD13. The Kbtbd13-knockout mouse model enables us to further decipher the pathomechanism underlying cardiac dysfunction upon Kbtbd13-deficiency.