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

Joon W. Shim, Paul Territo, Stefanie Simpson, John C. Watson, Lei Jiang, Amanda A. Riley, Brian McCarthy, Scott Persohn, Daniel Fulkerson, Bonnie L. Blazer-Yost

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number1069
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Hydrocephalus
Polycystic Kidney Diseases
Mutation
Choroid Plexus
Proteins
Epithelial Cells
Phenotype
Claudin-1
Aquaporin 1
Cystic Kidney Diseases
Point Mutation
Electrolytes
Cerebrospinal Fluid
Meckel syndrome type 1
Rodentia
Permeability
Homeostasis
Genotype
Kidney
Genes

ASJC Scopus subject areas

  • General

Cite this

Shim, J. W., Territo, P., Simpson, S., Watson, J. C., Jiang, L., Riley, A. A., ... Blazer-Yost, B. L. (2019). Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation. Scientific Reports, 9(1), [1069]. https://doi.org/10.1038/s41598-018-37620-5

Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation. / Shim, Joon W.; Territo, Paul; Simpson, Stefanie; Watson, John C.; Jiang, Lei; Riley, Amanda A.; McCarthy, Brian; Persohn, Scott; Fulkerson, Daniel; Blazer-Yost, Bonnie L.

In: Scientific Reports, Vol. 9, No. 1, 1069, 01.12.2019.

Research output: Contribution to journalArticle

Shim, JW, Territo, P, Simpson, S, Watson, JC, Jiang, L, Riley, AA, McCarthy, B, Persohn, S, Fulkerson, D & Blazer-Yost, BL 2019, 'Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation', Scientific Reports, vol. 9, no. 1, 1069. https://doi.org/10.1038/s41598-018-37620-5
Shim, Joon W. ; Territo, Paul ; Simpson, Stefanie ; Watson, John C. ; Jiang, Lei ; Riley, Amanda A. ; McCarthy, Brian ; Persohn, Scott ; Fulkerson, Daniel ; Blazer-Yost, Bonnie L. / Hydrocephalus in a rat model of Meckel Gruber syndrome with a TMEM67 mutation. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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