Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.

Authors:
Dr Lal D Nair
Dr Lal D Nair
Saveetha University
Developmental & Behavioural pediatrician
Neurodevelopmental/genetic disorders; Developmental &Behavioural; pediatrics
Chennai, Tamilnadu | India
Dr. Philippe M Campeau, MD, FCCMG
Dr. Philippe M Campeau, MD, FCCMG
University of Montreal
Canada
Dr. Lorenzo Stella, PhD
Dr. Lorenzo Stella, PhD
University of Rome Tor Vergata
Associate Professor
Biophysics, Biophysical Chemistry, Fluorescence, Molecular Dynamics, Proteins, Peptides, Membranes
Rome, RM | Italy

Nat Genet 2015 Jun 27;47(6):661-7. Epub 2015 Apr 27.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.

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http://dx.doi.org/10.1038/ng.3282DOI Listing
June 2015
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