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Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation
Joon W Shim1,2,3, Paul R Territo4, Stefanie Simpson1
1Department of Biology, Indiana University - Purdue University Indianapolis, Indianapolis, IN, 46202, USA.
Abstract:
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.
Insights
Mutations in Transmembrane protein 67 (TMEM67) cause Meckel Gruber Syndrome type 3. This study reveals TMEM67 gene dose impacts hydrocephalus severity and kidney disease in rats.
Area of Science:
- Nephrology
- Developmental Biology
- Genetics
Background:
- Meckel Gruber Syndrome type 3 (MKS3) is linked to mutations in Transmembrane protein 67 (TMEM67), causing hydrocephalus and kidney disease.
- The exact mechanisms by which TMEM67 mutations lead to these phenotypes are not fully understood.
Purpose of the Study:
- To investigate the role of TMEM67 in hydrocephalus and polycystic kidney disease development.
- To characterize the phenotype of TMEM67 mutations in the Wistar polycystic kidney (Wpk) rat model.
Main Methods:
- Generation and analysis of Wistar polycystic kidney (Wpk) rats with heterozygous and homozygous TMEM67 mutations.
- Assessment of hydrocephalus, renal phenotype, and cerebrospinal fluid composition.
- Evaluation of protein localization in choroid plexus epithelial cells.
Main Results:
- TMEM67 heterozygous mutations in Wpk rats result in slowly progressing hydrocephalus without renal defects.
- TMEM67 homozygous mutations cause severe ventriculomegaly, polycystic kidney disease, and neonatal lethality.
- Choroid plexus epithelial cells maintain normal aquaporin 1 and claudin-1 polarization, but exhibit increased permeability in hydrocephalic rats.
Conclusions:
- TMEM67 is crucial for regulating fluid and electrolyte balance in choroid plexus epithelial cells.
- The Wpk rat model effectively recapitulates human MKS3, offering insights into both mild and severe hydrocephalus.
- TMEM67 mutations impact gene dose-dependent development of hydrocephalus and polycystic kidney disease.
