XB-ART-56203
Mol Genet Genomic Med
January 1, 2019;
7
(9):
e892.
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
.
Abstract
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.
PubMed ID:
31393094
PMC ID:
PMC6732308
Article link:
Mol Genet Genomic Med
Grant support:
[+]
Species referenced:
Xenopus laevis
Genes referenced:
hhip
l1cam
slc12a6
tlx2
Article Images:
[+] show captions
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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 CHYD130‐1 demonstrating marked ventriculomegaly. (c) Pedigree depicting a heterozygous de novo deletion in SLC12A7, encoding the KCC3 paralog KCC4, which is present in CHYD130‐1 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) Spatial‐temporal gene expression for SLC12A7 in the brain development process across several brain regions using the bulk RNA‐sequencing data from the PsychENCODE project. The x‐axis denotes postconception days. The y‐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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References [+] :
Agez,
Molecular architecture of potassium chloride co-transporter KCC2.
2019,
Pubmed
Agez,
Molecular architecture of potassium chloride co-transporter KCC2.
2019,
Pubmed
Al-Dosari,
Mutation in MPDZ causes severe congenital hydrocephalus.
2013,
Pubmed
Boettger,
Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4.
2002,
Pubmed
Choi,
Genetic diagnosis by whole exome capture and massively parallel DNA sequencing.
2010,
Pubmed
Cui,
Electromagnetic Fields for the Regulation of Neural Stem Cells.
2019,
Pubmed
Delpire,
Housing and husbandry of Xenopus laevis affect the quality of oocytes for heterologous expression studies.
2011,
Pubmed
,
Xenbase
Ding,
A trafficking-deficient mutant of KCC3 reveals dominant-negative effects on K-Cl cotransport function.
2013,
Pubmed
,
Xenbase
Dong,
Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies.
2016,
Pubmed
Ekici,
Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum.
2019,
Pubmed
Fromer,
Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth.
2013,
Pubmed
Furey,
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
2019,
Pubmed
Howard,
The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum.
2002,
Pubmed
,
Xenbase
Jin,
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
2017,
Pubmed
Jin,
SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.
2020,
Pubmed
,
Xenbase
Kahle,
Hydrocephalus in children.
2016,
Pubmed
Kahle,
Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter.
2017,
Pubmed
Kircher,
A general framework for estimating the relative pathogenicity of human genetic variants.
2014,
Pubmed
Lek,
Analysis of protein-coding genetic variation in 60,706 humans.
2016,
Pubmed
Li,
Fast and accurate long-read alignment with Burrows-Wheeler transform.
2010,
Pubmed
Li,
Integrative functional genomic analysis of human brain development and neuropsychiatric risks.
2019,
Pubmed
Liebau,
Formation of cellular projections in neural progenitor cells depends on SK3 channel activity.
2007,
Pubmed
McKenna,
The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
2010,
Pubmed
Munch,
Familial aggregation of congenital hydrocephalus in a nationwide cohort.
2012,
Pubmed
Ng,
Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.
2010,
Pubmed
Purcell,
PLINK: a tool set for whole-genome association and population-based linkage analyses.
2007,
Pubmed
Robinson,
Integrative genomics viewer.
2011,
Pubmed
Rosenthal,
Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus.
1993,
Pubmed
Shaheen,
The genetic landscape of familial congenital hydrocephalus.
2017,
Pubmed
Simard,
Homooligomeric and heterooligomeric associations between K+-Cl- cotransporter isoforms and between K+-Cl- and Na+-K+-Cl- cotransporters.
2007,
Pubmed
,
Xenbase
Simon,
Hospital care for children with hydrocephalus in the United States: utilization, charges, comorbidities, and deaths.
2008,
Pubmed
Tarpey,
Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation.
2007,
Pubmed
Van der Auwera,
From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.
2016,
Pubmed
Wang,
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.
2010,
Pubmed
Wei,
A Bayesian framework for de novo mutation calling in parents-offspring trios.
2015,
Pubmed
