Universität zu Köln

Bauer, Christiane K., Schneeberger, Pauline E., Kortuem, Fanny, Altmueller, Janine, Santos-Simarro, Fernando ORCID: 0000-0002-1201-9118, Baker, Laura, Keller-Ramey, Jennifer, White, Susan M., Campeau, Philippe M., Gripp, Karen W. and Kutsche, Kerstin (2019). Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca2+-Activated K+ Channel SK3 Cause Zimmermann-Laband Syndrome. Am. J. Hum. Genet., 104 (6). S. 1139 - 1158. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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 (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.Va1450Leu 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bauer, Christiane K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneeberger, Pauline E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kortuem, Fanny UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Santos-Simarro, Fernando UNSPECIFIED orcid.org/0000-0002-1201-9118 UNSPECIFIED Baker, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Keller-Ramey, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED White, Susan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Campeau, Philippe M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gripp, Karen W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kutsche, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-138081
DOI:	10.1016/j.ajhg.2019.04.012
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	104
Number:	6
Page Range:	S. 1139 - 1158
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-KINASE CK2; POTASSIUM CHANNEL; GARDOS CHANNEL; TEMPLE-BARAITSER; PRIMARY CILIUM; EXPRESSION; CA2+; OVEREXPRESSION; MECHANISM; DOPAMINE Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13808