SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus
SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus
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DOI：
10.1002/mgg3.892
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发表时间：
2019-08-08
影响因子：
2
通讯作者：
Kahle, Kristopher T.
中科院分区：
文献类型：
--
作者：
Jin, Sheng Chih;Furey, Charuta G.;Kahle, Kristopher T.
研究背景先天性脑积水是一种以脑室扩大和脑脊液稳态受损为特征的高发病率疾病。虽然早期连锁或有针对性的测序研究，在大型多代家庭定位CH的几个基因，大多数CH病例的病因仍然不清楚。全外显子组测序（WES）的最新进展已经确定了五个新的真正的CH基因，涉及CH发病机制中神经干细胞命运的调节受损。尽管如此，在大多数CH病例中，病理病因仍然未知，这表明更多的基因有待发现。方法WES的家庭成员的散发和家族形式的严重L1 CAM突变阴性CH与导水管狭窄。对罕见的遗传变异进行了分析、优先排序和验证。使用XHMM算法鉴定从头拷贝数变体（CNV），并使用qPCR进行验证。进行爪蟾卵母细胞实验以评估突变对蛋白质功能和表达的影响。结果在多重家系CHYD 110的两个成员中发现了一个新的遗传性蛋白质损伤突变（p.Pro605Leu），该突变编码K+-Cl-协同转运蛋白KCC 3。p.Pro605在KCC 3直系同源物和所有人KCC旁系同源物中是保守的。P.Pro605Leu突变映射到离子转运结构域，并显著降低KCC 3依赖的K+转运。在另一个散发性CH家系（CHYD 130）中，在SLC 12 A7中发现了一个新的CNV（缺失），编码KCC 3和结合伴侣KCC 4。
Background Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery. Methods WES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression. Results A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K+-Cl- cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion-transporting domain, and significantly reduces KCC3-dependent K+ transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH. Conclusion These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.