1507-1509del (LQT-3)

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N.S. : non different from WT

COMMENTS and CLINICAL FINDINGS

The proband is a 41-year-old woman who was diagnosed with LQT3 and bradycardia during the development of deep vein thrombosis. She reported recurrent syncope triggered by fits of anger between the age of 12 and 16 years of age. Macroscopic sodium currents were recorded from tsA201 cells expressing WT (hNav1.5/WT), deletion and substitution mutant channels (hNav1.5/delQKP, delQ and Q1507A), co-transfected with the human b1-subunit.

The delQKP mutant sodium channels resulted in sodium currents exhibiting fast activation and inactivation kinetics and a persistent INa of 2.1 ± 0.9%. In mutant sodium channels a significant shift of the I/V relationship was observed.

Since the delQKP mutation shares the deletion Q1507 with the previously studied delKPQ1505-1507 in DIII-DIV linker, the authors investigated whether the deletion of the glutamine residue (delQ1507) and its substitution an alanine (Q1507A) exhibited similar persistent INa. Similar residual currents 1.6 ± 0.1% and 1.1 ± 0.5% were observed with delQ1507 Q1507A, respectively. A similar shift of the relationship was observed with delQ1507 mutant and significant shift was observed with the Q1507A mutant.
Overall, these data show that the Q1507 deletion alone is sufficient to induce a residual current with similar shifts in steady-state gating properties of Nav1.5 sodium channels, Thus suggesting that Q1507 is a crucial residue for channel inactivation.