Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families

• Published in: International journal of molecular sciences Vol. 25; no. 9; p. 4686
• Main Authors: Gallego-Delgado, María, Cámara-Checa, Anabel, Rubio-Alarcón, Marcos, Heredero-Jung, David, de la Fuente-Blanco, Laura, Rapún, Josu, Plata-Izquierdo, Beatriz, Pérez-Martín, Sara, Cebrián, Jorge, Moreno de Redrojo, Lucía, García-Berrocal, Belén, Delpón, Eva, Sánchez, Pedro L, Villacorta, Eduardo, Caballero, Ricardo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-05-2024
• Subjects: Adult; Age; Animals; Brugada syndrome; Cardiac arrhythmia; cardiac conduction defect; Cardiomyopathy; CHO Cells; Cricetulus; Daughters; dilated cardiomyopathy; Families & family life; Female; Humans; Loss of Function Mutation; Male; Middle Aged; Mutation; Nav1.5; NAV1.5 Voltage-Gated Sodium Channel - genetics; NAV1.5 Voltage-Gated Sodium Channel - metabolism; Pacemakers; Pedigree; Penetrance; Phenotype; SCN5A; Spain; Spain; mutation; Nav1.5; Brugada syndrome; phenotypic variability; phenotypic penetrance; cardiac conduction defect; SCN5A; dilated cardiomyopathy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25094686

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na
current (I
) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying
mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak I
generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17,
< 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of I
, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the I
and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of
loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.