Journal Article

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Paolacci, Stefano, Bocchinfuso, Gianfranco, Nair, Lal D V, White, Susan M, Kortüm, Fanny, Thierry, Patrick, Grammatico, Paola, Tartaglia, Marco, Stella, Lorenzo, Caputo, Viviana, Flex, Elisabetta, Ciolfi, Andrea, Alawi, Malik, Mowat, David, Kutsche, Kerstin, Pizzuti, Antonio, Campeau, Philippe M, Korenke, Georg Christoph, Bauer, Christiane K, Nguyen, Thi Tuyet Mai, Leuzzi, Vincenzo, Dentici, Maria Lisa, Dallapiccola, Bruno

2015

Overview

Kerstin Kutsche, Marco Tartaglia and colleagues show that missense mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome, a disorder characterized by facial dysmorphism, intellectual disability, digit anomalies and hypertrichosis. Functional studies indicate that the KCNH1 mutations lead to altered channel activity. 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 1 , 2 , 3 , 4 . We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K + channel Eag1 (K v 10.1). 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 potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2 , encoding the B2 subunit of the multimeric vacuolar H + ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/109 / 38/23 / 38/77 / 42/70 / 45/22 / 631/208/1516 / 692/699/375/366 / 9/74 / Abnormalities, Multiple - genetics / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Cancer Research / Causes of / CHO Cells / Codon, Nonsense / Craniofacial Abnormalities - genetics / Cricetinae / Cricetulus / Data analysis / Data processing / Ether-A-Go-Go Potassium Channels - genetics / Female / Fibromatosis, Gingival - genetics / Gene Function / Gene mutations / Genetic Association Studies / Genetic disorders / Genetic research / Genomes / Hand Deformities, Congenital - genetics / Health aspects / Heterogeneity / Human Genetics / Humans / Identification and classification / letter / Male / Membrane Potentials / Models, Molecular / Mutation / Mutation, Missense / Pedigree / Protein Conformation / Structural analysis / Vacuolar Proton-Translocating ATPases - genetics / Xenopus laevis