Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome
Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome
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DOI：
10.1038/ng.3282
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发表时间：
2015-06-01
期刊：
影响因子：
30.8
通讯作者：
Kutsche, Kerstin
中科院分区：
文献类型：
--
作者：
Kortuem, Fanny;Caputo, Viviana;Kutsche, Kerstin
Zimmermann-Laband综合征（ZLS）是一种发育障碍，其特征为面部畸形伴牙龈增大、智力障碍、指甲和末梢指骨发育不全或发育不全以及多毛（1-4）。我们报道KCNH1的杂合错义突变占ZLS的相当大比例。KCNH1编码电压门控K+通道Eag1 （K(v)10.1）。膜片钳记录显示，除了一个KCNH1通道突变体（Gly469Arg）外，所有突变体的电压依赖性激活都发生了强烈的负移。Gly469Arg与野生型KCNH1共表达导致异四聚体通道在正电位下电导降低，而在负电位下电导明显。这些数据支持所有与zls相关的KCNH1突变体的功能获得效应。我们还发现，在两名ZLS患者中，编码多聚液泡H+ atp酶B2亚基的ATP6V1B2基因出现了复发性的从头错义改变。结构分析预测突变对复杂装配的扰动效应。我们的研究结果表明，KCNH1突变导致ZLS，并记录了这种疾病的遗传异质性。
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(1-4). 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.