Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.
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.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Fanny
F
Kortüm
Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy.
Viviana
V
Caputo
Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christiane K
CK
Bauer
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome, Italy.
Lorenzo
0000000254897381
L
Stella
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
Andrea
A
Ciolfi
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.
Malik
M
Alawi
Dipartimento di Scienze e Tecnologie Chimiche, Università 'Tor Vergata', Rome, Italy.
Gianfranco
G
Bocchinfuso
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
Elisabetta
E
Flex
1] Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy. [2] Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
Stefano
S
Paolacci
Ospedale Pediatrico Bambino Gesù-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Maria Lisa
ML
Dentici
Dipartimento di Medicina Molecolare, Università La Sapienza, Ospedale San Camillo-Forlanini, Rome, Italy.
Paola
P
Grammatico
Zentrum für Kinder- und Jugendmedizin, Neuropädiatrie, Klinikum Oldenburg, Oldenburg, Germany.
Georg Christoph
GC
Korenke
Dipartimento di Pediatria e Neuropsichiatria Infantile, Università La Sapienza, Rome, Italy.
Vincenzo
V
Leuzzi
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.
David
D
Mowat
Department of Pediatrics, Saveetha Medical College and Hospital, Saveetha University, Chennai, India.
Lal D V
0000000253646919
LD
Nair
Sainte-Justine Hospital Research Center, University of Montreal, Montreal, Quebec, Canada.
Thi Tuyet Mai
TT
Nguyen
Service de Pédiatrie, Centre Hospitalier Intercommunal de la Haute-Saône, Vesoul, France.
Patrick
P
Thierry
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.
Susan M
SM
White
Ospedale Pediatrico Bambino Gesù-Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Bruno
B
Dallapiccola
Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy.
Antonio
A
Pizzuti
Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
Philippe M
0000000197137107
PM
Campeau
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.
Marco
M
Tartaglia
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Kerstin
K
Kutsche
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D018389:Codon, Nonsense; D019465:Craniofacial Abnormalities / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005351:Fibromatosis, Gingival / Q000235:genetics*; D056726:Genetic Association Studies; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*; D014982:Xenopus laevis
D018389:Codon, Nonsense; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D025262:Vacuolar Proton-Translocating ATPases; C000599123:ATP6V1B2 protein, human