2. Academic Validation
  3. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

  • Nat Genet. 2015 Jun;47(6):661-7. doi: 10.1038/ng.3282.
Fanny Kortüm 1,  Viviana Caputo 2,  Christiane K Bauer 3,  Lorenzo Stella 4,  Andrea Ciolfi 5,  Malik Alawi 6,  Gianfranco Bocchinfuso 4,  Elisabetta Flex 5,  Stefano Paolacci 7,  Maria Lisa Dentici 8,  Paola Grammatico 9,  Georg Christoph Korenke 10,  Vincenzo Leuzzi 11,  David Mowat 12,  Lal D V Nair 13,  Thi Tuyet Mai Nguyen 14,  Patrick Thierry 15,  Susan M White 16,  Bruno Dallapiccola 8,  Antonio Pizzuti 2,  Philippe M Campeau 17,  Marco Tartaglia 18,  Kerstin Kutsche 1
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 2 Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy.
  • 3 Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 4 Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome, Italy.
  • 5 Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
  • 6 1] University Medical Center Hamburg-Eppendorf, Bioinformatics Service Facility, Hamburg, Germany. [2] Center for Bioinformatics, University of Hamburg, Hamburg, Germany. [3] Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Virus Genomics, Hamburg, Germany.
  • 7 1] Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy. [2] Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
  • 8 Ospedale Pediatrico Bambino Gesù-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
  • 9 Dipartimento di Medicina Molecolare, Università La Sapienza, Ospedale San Camillo-Forlanini, Rome, Italy.
  • 10 Zentrum für Kinder- und Jugendmedizin, Neuropädiatrie, Klinikum Oldenburg, Oldenburg, Germany.
  • 11 Dipartimento di Pediatria e Neuropsichiatria Infantile, Università La Sapienza, Rome, Italy.
  • 12 1] Department of Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia. [2] School of Women's and Children's Health, University of New South Wales Medicine, University of New South Wales, Sydney, New South Wales, Australia.
  • 13 Department of Pediatrics, Saveetha Medical College and Hospital, Saveetha University, Chennai, India.
  • 14 Sainte-Justine Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.
  • 15 Service de Pédiatrie, Centre Hospitalier Intercommunal de la Haute-Saône, Vesoul, France.
  • 16 1] Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia. [2] Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
  • 17 Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
  • 18 1] Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy. [2] Ospedale Pediatrico Bambino Gesù-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
PMID: 25915598 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 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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