Match!

Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome

Published on Jun 1, 2019in American Journal of Human Genetics9.924
· DOI :10.1016/j.ajhg.2019.04.012
Christiane K. Bauer22
Estimated H-index: 22
(UHH: University of Hamburg),
Pauline E. Schneeberger (UHH: University of Hamburg)+ 8 AuthorsKerstin Kutsche32
Estimated H-index: 32
(UHH: University of Hamburg)
Abstract
Zimmermann-Laband syndrome (ZLS) is characterized by coarse facial features with gingival enlargement, intellectual disability (ID), hypertrichosis, and hypoplasia or aplasia of nails and terminal phalanges. De novo missense mutations in KCNH1 and KCNK4, encoding K+ channels, have been identified in subjects with ZLS and ZLS-like phenotype, respectively. We report de novo missense variants in KCNN3 in three individuals with typical clinical features of ZLS. KCNN3 (SK3/KCa2.3) constitutes one of three members of the small-conductance Ca2+-activated K+ (SK) channels that are part of a multiprotein complex consisting of the pore-forming channel subunits, the constitutively bound Ca2+ sensor calmodulin, protein kinase CK2, and protein phosphatase 2A. CK2 modulates Ca2+ sensitivity of the channels by phosphorylating SK-bound calmodulin. Patch-clamp whole-cell recordings of KCNN3 channel-expressing CHO cells demonstrated that disease-associated mutations result in gain of function of the mutant channels, characterized by increased Ca2+ sensitivity leading to faster and more complete activation of KCNN3 mutant channels. Pretreatment of cells with the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole revealed basal inhibition of wild-type and mutant KCNN3 channels by CK2. Analogous experiments with the KCNN3 p.Val450Leu mutant previously identified in a family with portal hypertension indicated basal constitutive channel activity and thus a different gain-of-function mechanism compared to the ZLS-associated mutant channels. With the report on de novo KCNK4 mutations in subjects with facial dysmorphism, hypertrichosis, epilepsy, ID, and gingival overgrowth, we propose to combine the phenotypes caused by mutations in KCNH1, KCNK4, and KCNN3 in a group of neurological potassium channelopathies caused by an increase in K+ conductance.
  • References (79)
  • Citations (0)
📖 Papers frequently viewed together
224 Citations
32 Citations
14 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References79
Newest
#1Mitsutaka Ogawa (Nagoya University)H-Index: 8
#2Tetsuya Okajima (Nagoya University)H-Index: 23
Extracellular O-GlcNAc is a unique modification restricted to the epidermal growth factor (EGF) domain-containing glycoproteins. This O-GlcNAcylation is catalyzed by the EGF-domain specific O-GlcNAc transferase (EOGT), which is localized in the lumen of endoplasmic reticulum. In humans, EOGT is one of the causative genes of a congenital disease, Adams–Oliver syndrome. EOGT is highly expressed in endothelial cells and regulates vascular development and integrity by potentiating Delta-like ligand-...
3 CitationsSource
#1Frederike L. Harms (UHH: University of Hamburg)H-Index: 4
#2Katja Kloth (UHH: University of Hamburg)H-Index: 3
Last. Kerstin Kutsche (UHH: University of Hamburg)H-Index: 32
view all 8 authors...
p21-activated kinases (PAKs) are serine/threonine protein kinases acting as effectors of CDC42 and RAC, which are members of the RHO family of small GTPases. PAK1’s kinase activity is autoinhibited by homodimerization, whereas CDC42 or RAC1 binding causes PAK1 activation by dimer dissociation. Major functions of the PAKs include actin cytoskeleton reorganization, for example regulation of the cellular protruding activity during cell spreading. We report the de novo PAK1 mutations c.392A>G (p.Tyr...
6 CitationsSource
#1Christiane K. Bauer (UHH: University of Hamburg)H-Index: 22
#2Paolo Calligari (University of Rome Tor Vergata)H-Index: 2
Last. Marco TartagliaH-Index: 39
view all 24 authors...
Aberrant activation or inhibition of potassium (K + ) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K + channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K + channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K + channels. While K2P channels...
9 CitationsSource
#1Young-Woo Nam (Chapman University)H-Index: 4
#2Sabia N. Baskoylu (Brown University)H-Index: 1
Last. Miao Zhang (Chapman University)H-Index: 7
view all 7 authors...
Small-conductance Ca2+-activated K+ (SK) channels mediate medium afterhyperpolarization in the neurons and play a key role in the regulation of neuronal excitability. SK channels are potential drug targets for ataxia and Amyotrophic Lateral Sclerosis (ALS). SK channels are activated exclusively by the Ca2+-bound calmodulin. Previously, we identified an intrinsically disordered fragment that is essential for the mechanical coupling between Ca2+/calmodulin binding and channel opening. Here, we rep...
1 CitationsSource
#1Chia-Hsueh Lee (HHMI: Howard Hughes Medical Institute)H-Index: 2
#2Roderick MacKinnon (HHMI: Howard Hughes Medical Institute)H-Index: 86
Small-conductance Ca 2+ -activated K + (SK) channels mediate neuron excitability and are associated with synaptic transmission and plasticity. They also regulate immune responses and the size of blood cells. Activation of SK channels requires calmodulin (CaM), but how CaM binds and opens SK channels has been unclear. Here we report cryo–electron microscopy (cryo-EM) structures of a human SK4-CaM channel complex in closed and activated states at 3.4- and 3.5-angstrom resolution, respectively. Fou...
21 CitationsSource
#1Christiane K. Bauer (UHH: University of Hamburg)H-Index: 22
#2Jürgen R. Schwarz (UHH: University of Hamburg)H-Index: 29
9 CitationsSource
#1Verna Cázares-Ordonez (MPG: Max Planck Society)H-Index: 1
#2Luis A. Pardo (MPG: Max Planck Society)H-Index: 36
The KCNH1 gene encodes the Kv10.1 (Eag1) ion channel, a member of the EAG (ether-a-go-go) family of voltage-gated potassium channels. Recent studies have demonstrated that KCHN1 mutations are implicated in Temple–Baraitser and Zimmermann–Laband syndromes and other forms of developmental deficits that all present with mental retardation and epilepsy, suggesting that Kv10.1 might be important for cognitive development in humans. Although the Kv10.1 channel is mainly expressed in the mammalian brai...
3 CitationsSource
Protein kinase CK2 is a small family of protein kinases that has been implicated in an expanding array of biological processes. While it is widely accepted that CK2 is a regulatory participant in a multitude of fundamental cellular processes, CK2 is often considered to be a constitutively active enzyme which raises questions about how it can be a regulatory participant in intricately controlled cellular processes. To resolve this apparent paradox, we have performed a systematic analysis of the p...
15 CitationsSource
#1Diana Urrego (MPG: Max Planck Society)H-Index: 4
#2Araceli Sánchez (MPG: Max Planck Society)H-Index: 10
Last. Luis A. Pardo (MPG: Max Planck Society)H-Index: 36
view all 4 authors...
4 CitationsSource
#1Sabine Martin (MPG: Max Planck Society)H-Index: 9
#2Marcio Lazzarini (MPG: Max Planck Society)H-Index: 7
Last. Elaine Del-Bel (USP: University of São Paulo)H-Index: 15
view all 10 authors...
The dysfunction of the small-conductance calcium-activated K+ channel SK3 has been described as one of the factors responsible for the progress of psychoneurological diseases, but the molecular basis of this is largely unknown. This report reveals through use of immunohistochemistry and computational tomography that long-term increased expression of the SK3 small-conductance calcium-activated potassium channel (SK3-T/T) in mice induces a notable bilateral reduction of the hippocampal area (more ...
9 CitationsSource
Cited By0
Newest