6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014).
Molecular Function
The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. Detected in brain, in particular in amygdala and hippocampus.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutations in HCN1 cause early infantile epileptic encephalopathy.
HCN1 loss of function is associated with ataxia and ASD. A homozygous knockout mouse model of HCN1 shows impairments in motor coordination and balance. The severity of the motor phenotype is dependent on the genetic background strain. The knockout also shows a decrease in GABA tone in the cerebellum. Chronic treatment with gabapentin, a voltage-gated calcium channel modulator, ameliorates the motor coordination phenotype.
References
Type
Title
Author, Year
Primary
Gabapentin treatment improves motor coordination in a mice model of progressive ataxia
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Two loxP sites were inserted flanking the pore-S6 domain containing exon. Excision of the targeted exon was done through Cre recombinase expression in targeted ES cells. Hcn1 mRNA and protein expression is absent in mice homozygous for this allele (MGI:2686951). This model has a mixed genetic background after one generation of inbreeding (F1).
Allele Type: Knockout
Strain of Origin: 129S/SvEv
Genetic Background: 129S/SvEv*C57BL6/J
ES Cell Line: MM13
Mutant ES Cell Line: Model Source: Jackson
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Two loxP sites were inserted flanking the pore-S6 domain containing exon. Excision of the targeted exon was done through Cre recombinase expression in targeted ES cells. Hcn1 mRNA and protein expression is absent in mice homozygous for this allele (MGI:2686951). This model has more uniform genetic background after three to six generations of inbreeding.
Allele Type: Knockout
Strain of Origin: 129S/SvEv
Genetic Background: B6129S
ES Cell Line: MM13
Mutant ES Cell Line: Model Source: Jackson
Description: 6-month-old knockout mice completely fail to balance on the Rotarod cylinder, while wildtype mice progressively improve motor performance during the 3 days of training. These mice are in the first generation of inbreeding.
Description: 2-month-old knockout mice completely fail to balance on the Rotarod cylinder, while wildtype mice progressively improve motor performance during the 3 days of training. These mice are in the sixth generation of inbreeding. The phenotype is also evident at 4 months of age. Inbred crossing caused a worsening of motor coordination impairment.
Description: The expression level of the mRNA for the GABA synthesis enzyme GAD67 is reduced in knockout mice compared to wildtype mice.
Exp Paradigm: GAD67 (GABA synthesis enzyme)
