ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9
ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9
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DOI：
10.1038/s41467-019-12428-7
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发表时间：
2019-10-01
影响因子：
16.6
通讯作者：
van Haaften, Gijs
中科院分区：
文献类型：
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作者：
Smeland, Marie F.;McClenaghan, Conor;van Haaften, Gijs
编码K-ATP通道亚单位的基因突变已被报道用于胰腺疾病和Cantu综合征。在这里，我们报告了来自两个家族的6名患者的综合征，这些患者具有一致的轻度智力残疾、相似的面容、肌病和脑白色物质高信号表型，其中两名年龄最大的患者存在心脏收缩功能障碍。患者是ABCC 9（c.1320 + 1 G > A）中剪接位点突变的纯合子，ABCC 9编码K-ATP通道的磺酰脲受体2（SUR 2）亚基。该突变导致外显子8的框内缺失，这导致重组测定中的非功能性K-ATP通道。SUR 2功能丧失导致小鼠的疲劳和心脏功能障碍，以及斑马鱼的活动减少、心脏功能障碍和心室扩大。我们将这种由含SUR 2的K-ATP通道功能丧失引起的通道病称为ABCC 9相关智力残疾肌病综合征（AIMS）。该表型不同于Cantu综合征，后者由功能获得性ABCC 9突变引起，反映了K-ATP丧失与功能获得的相反后果。
Mutations in genes encoding K-ATP channel subunits have been reported for pancreatic disorders and Cantu syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of K-ATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K-ATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing K-ATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantu syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of K-ATP loss- versus gain-of-function.