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Mol Genet Genomic Med
2019 Sep 08;79:e892. doi: 10.1002/mgg3.892.
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SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.
Jin SC, Furey CG, Zeng X, Allocco A, Nelson-Williams C, Dong W, Karimy JK, Wang K, Ma S, Delpire E, Kahle KT.
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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.
Figure 1. Identification of a novel inherited SLC12A6 (KCC3) mutation in familial CH with aqueductal stenosis. Coronal head computed tomography images in (a) proband CHYD110â€1 and (b) affected sibling CHYD110â€2. Note ventriculomegaly, agenesis of the corpus callosum, and schizencephaly. (c) Pedigree and DNA chromatograms depicting a heterozygous c.C1814T (p.Pro605Leu) mutation in SLC12A6, encoding the K+â€Cl− cotransporter KCC3, in the indicated individuals. Triangle represents a spontaneous abortion that occurred after the birth of the two affected children. (d) Evolutionary conservation of KCC3 p.Pro605 across multiple species and (e) among human N(K)CC family transporters (KCC1â€4). (f) Decreased function of KCC3 p.Pro605Leu transporter. Left, K+ influx in oocytes injected with WT or p.Pro605Leu mouse KCC3 cRNA. Flux was measured in isotonic (gray) or hypotonic (black) activating conditions. Bars represent mean ± SEM, n = 24 oocytes. Difference between black bars is highly significant (p < .001, ANOVA). (g) Western blot showing expression of câ€mycâ€tagged WT and mutant KCC3 in oocyte membrane fractions. Primary antibody was directed against câ€myc epitope. (h) Spatialâ€temporal gene expression for SLC12A6 in the brain development process across several brain regions using the bulk RNAâ€sequencing data from the PsychENCODE project. The xâ€axis denotes postconception days. The yâ€axis denotes normalized expression level (represented by log2 of RPKM). NCX: Neocortex; HIP: Hippocampus; AMY: Amygdala; STR: Striatum; MD: Mediodorsal nucleus of the thalamus; CBC: Cerebellar cortex
Figure 2. Identification of a novel de novo SLC12A7 (KCC4) deletion in sporadic CH with aqueductal stenosis. Coronal (a) and axial (b) magnetic resonance images in proband CHYD130â€1 demonstrating marked ventriculomegaly. (c) Pedigree depicting a heterozygous de novo deletion in SLC12A7, encoding the KCC3 paralog KCC4, which is present in CHYD130â€1 but absent in his unaffected parents. (d) XHMM plot of exome sequencing data demonstrating de novo copy number deletion which expands four targets from chr5:1073722 to chr5:1076364. (e) Spatialâ€temporal gene expression for SLC12A7 in the brain development process across several brain regions using the bulk RNAâ€sequencing data from the PsychENCODE project. The xâ€axis denotes postconception days. The yâ€axis denotes normalized expression level (represented by log2 of RPKM). NCX: Neocortex; HIP: Hippocampus; AMY: Amygdala; STR: Striatum; MD: Mediodorsal nucleus of the thalamus; CBC: Cerebellar cortex
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