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首页> 外文期刊>PLoS Genetics >A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions
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A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions

机译：<斜视> CaCnB4 编码辅助钙通道Beta4亚基的纯合物的畸形变异导致严重的神经发育障碍和危及通道和非渠道功能

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P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming Ca _(V)2.1 α _(1) subunit and the auxiliary α2δ-2 and β _(4) subunits. β _(4) is encoded by CACNB4 , and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1 , EMILIN1 , CACNB4 , MINAR1 , DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat β _(4b) cDNA. Heterologously expressed wild-type β _(4b) associated with GFP-Ca _(V)1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the β _(4b)-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with Ca _(V)2.1 in tsA201 cells, β _(4b) and β _(4b)-L125P augmented the calcium current amplitudes, however, β _(4b)-L125P failed to stably complex with α _(1) subunits. These results indicate that p.Leu125Pro disrupts the stable association of β _(4b) with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype β _(4b) was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of β _(4b) in cultured myotubes and hippocampal neurons. While binding of β _(4b) to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between β _(4b)-L125P and the neuronal TRAF2 and NCK interacting kinase (TNIK) seemed to be disturbed. In summary, our data suggest that the homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings, most likely by impairing both channel and non-channel functions of β _(4b).
机译：P / Q型通道是神经递质释放中脑功能的主要突触前钙通道。它们由形成Ca _（v）2.1α_（1）亚基和辅助α2δ-2和β_（4）亚基组成。 β_（4）由CaCNB4编码，其多种剪接变体为核中的信道亚基和转录调节剂提供了种类的特定作用。在两个兄弟姐妹患有智力残疾，精神抑制，失明，癫痫，运动障碍和小脑萎缩，我们通过全外壳测序确定了基因LTBP1，Emilin1，CacnB4，MinAR1，DHX38和MyO15中的罕见纯合的变体。在Silico工具，动物模型，临床和遗传数据中表明p。（Leu126pro）CaCnB4变体可能致病。为了探讨CacnB4变体的功能后果，我们将相应的突变L125P引入大鼠β_（4B）cDNA中。与GFP-Ca _（v）1.2相关的异源表达野生型β_（4b），并积累在培养的海马神经元的突触前。相反，β_（4b）-1125p突变体未被掺入钙通道复合物中并呈前突兀。当用TS201细胞中的Ca _（v）2.1共表达时，β_（4b）和β_（4b）-1125p增强钙电流幅度，然而，β_（4b）-1125p与α_稳定复杂（1）亚基。这些结果表明，P.LEU125PRO破坏了β_（4b）与天然钙通道络合物的稳定关联，而膜掺入，异源表达通道的电流密度和活化性能的调节保持完整。野生型β_（4b）特异性靶向静态兴奋细胞的核。重要的是，P.LEU125PRO突变废除培养的肌管和海马神经元β_（4B）的核靶向。虽然将β_（4b）与已知的相互作用伙伴Ppp2R5d（b56δ）的结合不受突变的影响，但β_（4b）-1125p和神经元traf2和nck相互作用的激酶（tnik）之间的复杂形成似乎受到干扰。总之，我们的数据表明纯合CACNB4 p。（LEU126PRO）变异在两个兄弟姐妹中的严重神经能表型下潜，最有可能损害β_（4b）的频道和非通道功能。

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