Molecular mechanisms of function deficiencies in KCNQ1 variants associated with Jervell and Lange–Nielsen syndrome

Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital bilateral sensorineural hearing loss, a prolonged QT interval (QTc) on an electrocardiogram (ECG), and a high incidence of sudden death in childhood. More than 90% of JLNS cases are associated with variants in the potassium voltage-gated channel subfamily Q member 1 gene, KCNQ1 (Kv7.1). Herein, eighteen identified JLNS-related KCNQ1 variants were examined, including I145S, Y148S, G168R, Y171X, S182R, G186D, R190Q, G269D, G272D, A302V, G306V, V307V, S333F, A344A, F351L, K422S, T587M, and R594Q. Using an integrative method, we systematically characterized the biophysical properties, functional, and membrane trafficking of KCNQ1 variants distributed in different structural domains of the channel. The results demonstrated that all the variants resulted in functional deficiencies, with impaired localization in the plasma membrane being the most common cause. Although many variants exhibited normal cell surface expression consistent with protein stability, structural simulation analysis revealed that these KCNQ1 variants disrupt either KCNQ1-KCNE1 or KCNQ1-calmodulin (CaM) interaction, leading to channel dysfunction. These finding provide significant implications for the future treatment and prevention of JLNS.