Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

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

Research output: Contribution to journalArticle

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 (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.

Original languageEnglish
Pages (from-to)661-667
Number of pages7
JournalNature Genetics
Volume47
Issue number6
DOIs
Publication statusPublished - May 27 2015

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Mutation
Hypertrichosis
Vacuolar Proton-Translocating ATPases
Voltage-Gated Potassium Channels
Inborn Genetic Diseases
Genetic Heterogeneity
Missense Mutation
Nails
Intellectual Disability
Zimmerman Laband syndrome

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Kortüm, F., Caputo, V., Bauer, C. K., Stella, L., Ciolfi, A., Alawi, M., ... Kutsche, K. (2015). Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nature Genetics, 47(6), 661-667. https://doi.org/10.1038/ng.3282

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. / Kortüm, Fanny; Caputo, Viviana; Bauer, Christiane K.; Stella, Lorenzo; Ciolfi, Andrea; Alawi, Malik; Bocchinfuso, Gianfranco; Flex, Elisabetta; Paolacci, Stefano; Dentici, Maria Lisa; Grammatico, Paola; Korenke, Georg Christoph; Leuzzi, Vincenzo; Mowat, David; Nair, Lal D V; Nguyen, Thi Tuyet Mai; Thierry, Patrick; White, Susan M.; Dallapiccola, Bruno; Pizzuti, Antonio; Campeau, Philippe M.; Tartaglia, Marco; Kutsche, Kerstin.

In: Nature Genetics, Vol. 47, No. 6, 27.05.2015, p. 661-667.

Research output: Contribution to journalArticle

Kortüm, F, Caputo, V, Bauer, CK, Stella, L, Ciolfi, A, Alawi, M, Bocchinfuso, G, Flex, E, Paolacci, S, Dentici, ML, Grammatico, P, Korenke, GC, Leuzzi, V, Mowat, D, Nair, LDV, Nguyen, TTM, Thierry, P, White, SM, Dallapiccola, B, Pizzuti, A, Campeau, PM, Tartaglia, M & Kutsche, K 2015, 'Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome', Nature Genetics, vol. 47, no. 6, pp. 661-667. https://doi.org/10.1038/ng.3282
Kortüm F, Caputo V, Bauer CK, Stella L, Ciolfi A, Alawi M et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nature Genetics. 2015 May 27;47(6):661-667. https://doi.org/10.1038/ng.3282
Kortüm, Fanny ; Caputo, Viviana ; Bauer, Christiane K. ; Stella, Lorenzo ; Ciolfi, Andrea ; Alawi, Malik ; Bocchinfuso, Gianfranco ; Flex, Elisabetta ; Paolacci, Stefano ; Dentici, Maria Lisa ; Grammatico, Paola ; Korenke, Georg Christoph ; Leuzzi, Vincenzo ; Mowat, David ; Nair, Lal D V ; Nguyen, Thi Tuyet Mai ; Thierry, Patrick ; White, Susan M. ; Dallapiccola, Bruno ; Pizzuti, Antonio ; Campeau, Philippe M. ; Tartaglia, Marco ; Kutsche, Kerstin. / Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. In: Nature Genetics. 2015 ; Vol. 47, No. 6. pp. 661-667.
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