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 language | English |
|---|---|
| Pages (from-to) | 661-667 |
| Number of pages | 7 |
| Journal | Nature Genetics |
| Volume | 47 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - May 27 2015 |
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ASJC Scopus subject areas
- Genetics
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome
AU - Kortüm, Fanny
AU - Caputo, Viviana
AU - Bauer, Christiane K.
AU - Stella, Lorenzo
AU - Ciolfi, Andrea
AU - Alawi, Malik
AU - Bocchinfuso, Gianfranco
AU - Flex, Elisabetta
AU - Paolacci, Stefano
AU - Dentici, Maria Lisa
AU - Grammatico, Paola
AU - Korenke, Georg Christoph
AU - Leuzzi, Vincenzo
AU - Mowat, David
AU - Nair, Lal D V
AU - Nguyen, Thi Tuyet Mai
AU - Thierry, Patrick
AU - White, Susan M.
AU - Dallapiccola, Bruno
AU - Pizzuti, Antonio
AU - Campeau, Philippe M.
AU - Tartaglia, Marco
AU - Kutsche, Kerstin
PY - 2015/5/27
Y1 - 2015/5/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930092141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930092141&partnerID=8YFLogxK
U2 - 10.1038/ng.3282
DO - 10.1038/ng.3282
M3 - Article
C2 - 25915598
AN - SCOPUS:84930092141
VL - 47
SP - 661
EP - 667
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 6
ER -