SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.
SLC12A6
SLC12A7
KCC3
KCC4
hydrocephalus
whole exome sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
19
03
2019
revised:
15
06
2019
accepted:
07
07
2019
pubmed:
9
8
2019
medline:
18
6
2020
entrez:
9
8
2019
Statut:
ppublish
Résumé
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. 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. A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K 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.
Sections du résumé
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
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.
Identifiants
pubmed: 31393094
doi: 10.1002/mgg3.892
pmc: PMC6732308
doi:
Substances chimiques
L1CAM protein, human
0
Neural Cell Adhesion Molecule L1
0
SLC12A6 protein, human
0
SLC12A7 protein, human
0
Symporters
0
Types de publication
Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e892Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL143036
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK110375
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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