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Nat Genet
2015 Jan 01;471:73-7. doi: 10.1038/ng.3153.
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Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
Simons C
,
Rash LD
,
Crawford J
,
Ma L
,
Cristofori-Armstrong B
,
Miller D
,
Ru K
,
Baillie GJ
,
Alanay Y
,
Jacquinet A
,
Debray FG
,
Verloes A
,
Shen J
,
Yesil G
,
Guler S
,
Yuksel A
,
Cleary JG
,
Grimmond SM
,
McGaughran J
,
King GF
,
Gabbett MT
,
Taft RJ
.
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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. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), 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, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.
Figure 2: KCNH1 mutations in subjects with TBS. (a) Genomic structure of the KCNH1 gene. The positions of the TBS-associated de novo mutations are indicated in red. The transcription start site is shown as a blue arrow. (b) Schematic of the KCNH1 protein showing the six transmembrane helices (S1âS6), the intracellular N-terminal region containing an EAG domain and the C-terminal region containing a cyclic nucleotideâbinding homology domain (CNBHD). The locations of the TBS-associated de novo alterations are indicated by red stars. (c) Multiple-sequence alignment of all eight human KCNH family proteins. The mutated KCNH1 residues are highlighted in bold. Conservation of residues across the gene family is indicated in red.
Supplementary Figure 1: Activation, deactivation and Inactivation of wild-type and mutant KCNH1 channels expressed in Xenopus oocytes.
(a) Representative families of whole-cell currents showing voltage-dependent activation of wild-type (WT) and mutant human KCNH1 channels expressed in Xenopus oocytes. Currents were elicited by steps from â120 mV to +80 mV in 20-mV increments, using a holding potential of â100 mV. Inset in the final panel: schematic of the pulse protocol used for the activation experiments. (b) Representative families of whole-cell currents showing only minor steady-state inactivation of WT and mutant KCNH1 channels expressed in Xenopus oocytes. Inset in the final panel: schematic of the pulse protocol used for the inactivation experiments. (c) Activation current-voltage relationship (± s.e.m.) for WT, p.Lys217Asn, p.Leu489Phe, p.Ile494Val and p.Gln503Arg channels expressed in Xenopus oocytes. Currents were measured at the end of the activation test pulse. (d) Fast and slow time constants (Ï) of deactivation for WT and mutant KCNH1 channels expressed in Xenopus oocytes, analyzed from the tail current at â90 mV following a maximally activating prepulse to +80 mV. (e) Steady-state inactivation current-voltage relationship (± s.e.m.) for WT and mutant KCNH1 channels expressed in Xenopus oocytes. Currents were measured at the end of the +30 mV activation test pulse. Data are presented as mean ± s.e.m. with the numbers of experiments indicated in parentheses. P values were calculated in comparison to WT using an unpaired t test with Welchâs correction. *P < 0.05, **P < 0.01, ***P < 0.001.
References :
Simons,
Corrigendum: Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
2015, Pubmed
Simons,
Corrigendum: Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
2015,
Pubmed
