Background: The role of SCN5A in sinus bradycardia is still in debate. The cumulative effect of multiple SCN5A mutations is poorly delineated.
Methods: We performed genetic screening and functional studies of a 16 year old presenting with severe sinus and AV nodal conduction disease. Whole-cell currents recordings were performed for Nav1.5 wild type and mutants heterologously expressed in human embryonic kidney 293 cells (HEK). Immunofluorescence and Confocal Analysis was performed on all variants.
Results: The proband was found to carry three SCN5A variants. Family screening revealed that the father carried two variants (V1251M, V1924T) whereas the mother had a K1492del. Neither parent displayed evidence of conduction disease. Co-expression of all three variants (V1251M, V1924T/ K1492del) (n= 26) showed significant loss of function in peak sodium channel current (INa) density (89± 17.5 pA/pF ) and significant leftward shift of mid inactivation voltage (-89± 1.3 mV) compared to all other variants [V1251M , V1924T/ WT (119± 14 pA/pF, -78± 1.8 mV; n=68) ; K1492del/ WT (140± 18 pA/pF, -80± 1.3 mV; n=50) and WT/WT (145± 19 pA/pF, -79± 1.2 mV; n=56)]. Confocal microscopy showed normal trafficking of all NaV1.5 variants.
Conclusion: Mutations in SCN5A can interact with each other to produce a phenotype associated with severe conduction disease. Only a combination of all 3 genetic variants severely affected the biophysical but not trafficking properties of the channel.
