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

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
head development  IMP 14995942; 14995942 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
apical plasma membrane  IDA 14995942 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal blood-cerebrospinal fluid barrier function  IAGP 14995942; 14995942 RGD 
abnormal blood-cerebrospinal fluid barrier function  IAGP 14995942compared to Wpk and Wpk +/-RGD 
abnormal cerebrospinal fluid flow  IAGP 14995942; 14995942 RGD 
abnormal cerebrospinal fluid flow  IAGP 14995942compared to WpkRGD 
abnormal ciliary body morphology  IAGP 14995942; 14995942; 14995942 RGD 
abnormal head shape  IAGP 14995942; 14995942 RGD 
abnormal head shape  IAGP 14995942compared to WpkRGD 
abnormal head size  IAGP 14995942; 14995942; 14995942 RGD 
decreased body height  IAGP 14995942; 14995942; 14995942 RGD 
decreased body weight  IAGP 14995942; 14995942 RGD 
decreased body weight  IAGP 14995942compared to Wpk and Wpk +/-RGD 
dilated lateral ventricle  IAGP 14995942; 14995942; 14995942 RGD 
dilated lateral ventricle  IAGP 14995942compared to WpkRGD 
enlarged lateral ventricles  IAGP 14995942; 14995942; 14995942 RGD 
increased brain ependyma motile cilium length  IAGP 14995942; 14995942 RGD 
increased brain ependyma motile cilium length  IAGP 14995942compared to Wpk and Wpk +/-RGD 
increased brain weight  IAGP 14995942; 14995942 RGD 
increased brain weight  IAGP 14995942compared to Wpk and Wpk +/-RGD 
increased kidney weight  IAGP 14995942; 14995942; 14995942 RGD 
increased vascular permeability  IAGP 14995942; 14995942 RGD 
increased vascular permeability  IAGP 14995942compared to Wild-type and Wpk +/-RGD 
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)

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


Additional Information