Journal article
Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome
Fanny Kortuem, Viviana Caputo, Christiane K Bauer, Lorenzo Stella, Andrea Ciolfi, Malik Aawi, Gianfranco Bocchinfuso, Elisabetta Flex, Stefano Paolacci, Maria Lisa Dentici, Paola Grammatico, Georg Christoph Korenke, Vincenzo Leuzzi, David Mowat, Lal DV Nair, Tuyet Mai Nguyen Thi, Patrick Thierry, Susan M White, Bruno Dallapiccola, Antonio Pizzuti Show all
NATURE GENETICS | NATURE PUBLISHING GROUP | Published : 2015
DOI: 10.1038/ng.3282
Abstract
Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potenti..
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Awarded by Deutsche Forschungsgemeinschaft
Awarded by Ministero della Salute (Ricerca Finalizzata)
Funding Acknowledgements
We are grateful to the patients and their families who contributed to this study. We thank I. Jantke, S. Cecchetti and S. Venanzi for skillful technical assistance, T. Kock for site-directed mutagenesis, A. Hasse for CHO cell transfection and injection, R. Bahring, J.M. Schroder and E. Neumann for help with the oocyte experiments, P. Meinecke for discussing clinical phenotypes and A. Podolska for help with ATP6V1B2 sequencing. G.B., L.S. and M.T. acknowledge CINECA for computational resources (whole-exome sequencing data and structural analyses). The KCNH1/heag1 clone was kindly provided by S.H. Heinemann (Friedrich Schiller University Jena). This work was supported by grants from the Deutsche Forschungsgemeinschaft (KO 4576/1-1 to F.K. and KU 1240/5-1 to K.K.), Istituto Superiore di Sanita (Ricerca Corrente 2013 to M.T.), Ministero della Salute (Ricerca Finalizzata RF-2010-2312766 to B.D.) and Ospedale Pediatrico Bambino Gesu (Gene-Rare to B.D.).