Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Nat Genet. 2015 Jun;47(6):661-7. doi: 10.1038/ng.3282. Epub 2015 Apr 27.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Animals
  • CHO Cells
  • Codon, Nonsense
  • Craniofacial Abnormalities / genetics*
  • Cricetinae
  • Cricetulus
  • Ether-A-Go-Go Potassium Channels / genetics*
  • Female
  • Fibromatosis, Gingival / genetics*
  • Genetic Association Studies
  • Hand Deformities, Congenital / genetics*
  • Humans
  • Male
  • Membrane Potentials
  • Models, Molecular
  • Mutation, Missense
  • Pedigree
  • Protein Conformation
  • Vacuolar Proton-Translocating ATPases / genetics*
  • Xenopus laevis


  • Codon, Nonsense
  • Ether-A-Go-Go Potassium Channels
  • KCNH1 protein, human
  • Vacuolar Proton-Translocating ATPases
  • ATP6V1B2 protein, human

Supplementary concepts

  • Zimmerman Laband syndrome