FKTN GENE CHARACTERIZATION IN DILATED CARDIOMYOPATHY USING ZEBRAFISH MODEL

Abstract

Dilated cardiomyopathy (DCM) is a prevalent myocardial disorder marked by left ventricular dilation and impaired contractility, often progressing to heart failure. While genetic mutations affecting cardiac muscle integrity are a primary cause, variants in the FKTN gene—encoding Fukutin, essential for α-dystroglycan glycosylation—have been increasingly implicated due to their association with dystroglycanopathies and cardiac dysfunction. This study aimed to (i) establish an fktn-deficient zebrafish model to investigate DCM phenotypes, and (ii) evaluate the potential pathogenicity of the FKTN variant c.1371_1381dupTATCCAGTTAT (p.Tyr461Leufs), a variant of uncertain significance (VUS) identified in three Qatari patients. The variant was found in a homozygous state in two individuals with DCM and a heterozygous state in one patient with hypertrophic cardiomyopathy (HCM), suggesting a possible founder effect. Morpholino-mediated fktn knockdown in zebrafish larvae resulted in pronounced ventricular chamber enlargement and reduced wall thickness during diastole, mirroring key clinical features of human DCM. Despite these structural abnormalities, cardiac function remained preserved, with increased fractional area change and stroke volume and normal ejection fraction. Histological analysis confirmed disrupted myocardial architecture, supporting the role of FKTN in maintaining cardiac structure. However, attempts to validate the pathogenicity of the p.Tyr461Leufs variant in vivo were inconclusive, warranting further investigation. These findings emphasize the utility of zebrafish for modeling genetic cardiomyopathies and highlight the importance of genetic screening and functional assessment to inform precision medicine efforts, particularly in populations with recurrent founder variants.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences