Naslov
De novo mutations in HCN1 cause early infantile epileptic encephalopathy

Autori
Caroline, Nava ; Carine, Dalle ; Agnès, Rastetter ; Pasquale, Striano ; Carolien G.F., de Kovel ; Rima, Nabbout ; Claude ; Cancès ; Dorothée, Ville ; Eva, H Brilstra ; Giuseppe, Gobbi ; Barišić, Nina ; ... ; Depienne, Christel

Izvornik
Nature genetics (1061-4036) 46 (2014), 6; 640-645

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, stručni

Ključne riječi
de novo mutation; epileptic encephalopathies

Sažetak
Hyperpolarization-activated, cyclic nucleotide– gated (HCN) channels contribute to cationic Ih current in neurons and regulate the excitability of neuronal networks. Studies in rat models have shown that the Hcn1 gene has a key role in epilepsy, but clinical evidence implicating HCN1 mutations in human epilepsy is lacking. We carried out exome sequencing for parent-offspring trios with fever-sensitive, intractable epileptic encephalopathy, leading to the discovery of two de novo missense HCN1 mutations. Screening of follow-up cohorts comprising 157 cases in total identified 4 additional amino acid substitutions. Patch- clamp recordings of Ih currents in cells expressing wild-type or mutant human HCN1 channels showed that the mutations had striking but divergent effects on homomeric channels. Individuals with mutations had clinical features resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits. These findings provide clear evidence that de novo HCN1 point mutations cause a recognizable early-onset epileptic encephalopathy in humans.

Izvorni jezik
Engleski

Napomena
EuroEPINOMICS RES Consortium.

POVEZANOST RADA