RGD Reference Report - Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation. - Rat Genome Database

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Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation.

Authors: Shim, Joon W  Territo, Paul R  Simpson, Stefanie  Watson, John C  Jiang, Lei  Riley, Amanda A  McCarthy, Brian  Persohn, Scott  Fulkerson, Daniel  Blazer-Yost, Bonnie L 
Citation: Shim JW, etal., Sci Rep. 2019 Jan 31;9(1):1069. doi: 10.1038/s41598-018-37620-5.
RGD ID: 14995942
Pubmed: PMID:30705305   (View Abstract at PubMed)
PMCID: PMC6355840   (View Article at PubMed Central)
DOI: DOI:10.1038/s41598-018-37620-5   (Journal Full-text)

Transmembrane protein 67 (TMEM67) is mutated in Meckel Gruber Syndrome type 3 (MKS3) resulting in a pleiotropic phenotype with hydrocephalus and renal cystic disease in both humans and rodent models. The precise pathogenic mechanisms remain undetermined. Herein it is reported for the first time that a point mutation of TMEM67 leads to a gene dose-dependent hydrocephalic phenotype in the Wistar polycystic kidney (Wpk) rat. Animals with TMEM67 heterozygous mutations manifest slowly progressing hydrocephalus, observed during the postnatal period and continuing into adulthood. These animals have no overt renal phenotype. The TMEM67 homozygous mutant rats have severe ventriculomegaly as well as severe polycystic kidney disease and die during the neonatal period. Protein localization in choroid plexus epithelial cells indicates that aquaporin 1 and claudin-1 both remain normally polarized in all genotypes. The choroid plexus epithelial cells may have selectively enhanced permeability as evidenced by increased Na+, K+ and Cl- in the cerebrospinal fluid of the severely hydrocephalic animals. Collectively, these results suggest that TMEM67 is required for the regulation of choroid plexus epithelial cell fluid and electrolyte homeostasis. The Wpk rat model, orthologous to human MKS3, provides a unique platform to study the development of both severe and mild hydrocephalus.

Disease Annotations    

Gene Ontology Annotations    

Biological Process

Cellular Component

Objects Annotated

Genes (Rattus norvegicus)
Aqp1  (aquaporin 1)
Tmem67  (transmembrane protein 67)
Tmem67wpk  (transmembrane protein 67; wpk mutant)

Genes (Mus musculus)
Tmem67  (transmembrane protein 67)

Genes (Homo sapiens)
TMEM67  (transmembrane protein 67)

Wpk  (Wistar polycystic kidney rat)
Wpk +/-  (Wpk heterozygous rat)
Wpk -/-  (Wpk homozygous rat)

Additional Information