ClinVar

In a girl (patient 10) with developmental and epileptic encephalopathy-24 (DEE24; 615871), Marini et al. (2018) identified a de novo c.913A-T transversion (c.913A-T, NM_021072.3) in exon 3 of the HCN1 gene, resulting in a met305-to-leu (M305L) substitution in the fifth transmembrane segment. The mutation was found by Sanger sequencing of an epilepsy gene panel. In vitro functional studies showed that the mutation caused a decreased current density, although this returned to normal when expressed with wildtype protein. However, the mutation caused a right shift in voltage dependence and an increased slope factor, indicating abnormal gating properties. The patient had onset of tonic-clonic seizures at 3 months of age.

Variant Function

Bleakley et al. (2021) generated a mouse model with a heterozygous homologous M305L mutation (M294L in the mouse) in the Hcn1 gene that recapitulated the seizure phenotype with active epileptiform spiking on EEG. The mice also showed hyperactivity, some learning deficits, and behavioral abnormalities. Electrophysiologic studies in Xenopus oocytes and mutant cortical pyramidal neurons showed a loss of voltage dependence for the variant, resulting in a constitutively open channel that allowed cation leak at depolarized membrane potentials. Although the neurons adapted through a depolarizing shift in action potential threshold, action potentials fired more readily from rest compared to wildtype. The findings were consistent with neuronal hyperexcitability resulting from the HCN1 mutation, consistent with a gain-of-function effect.