Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy

Simons C., Rash L. D., Crawford J., Ma L., Cristofori-Armstrong B., Miller D., ...Daha Fazla

NATURE GENETICS, cilt.47, sa.1, ss.73-78, 2015 (SCI-Expanded) identifier identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 47 Sayı: 1
  • Basım Tarihi: 2015
  • Doi Numarası: 10.1038/ng.3153
  • Dergi Adı: NATURE GENETICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.73-78
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Evet

Özet

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe(1,2). Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether a go-go, EAG1 or K(V)10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports(3-8), this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.