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

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

doi:10.1038/s41598-018-37620-5

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.

Highlights

The classic but oversimplified definition of hydrocephalus describes two types, communicating and obstructive[2,3]
The Wistar polycystic kidney (Wpk) rat, carrying a single point mutation in the transmembrane protein 67 (TMEM67), is a genetic model of hydrocephalus and polycystic kidney disease (PKD) that is orthologous to human Meckel-Gruber Syndrome (MKS) type 3 (MKS3)[12,13]
The heterozygous (TMEM67+/−) rats have midline malformations and mild hydrocephalus that does not appear to impair normal physiological functions until after the first year of life. The latter is, to our knowledge, the first description of an animal genetic model of slowly progressing hydrocephalus. These models are unique in that they avoid the necessity of intracranial injection of sclerotic or hemorrhagic agents to induce the disease

Summary

Introduction

The classic but oversimplified definition of hydrocephalus describes two types, communicating and obstructive[2,3]. The heterozygous (TMEM67+/−) rats have midline malformations and mild hydrocephalus that does not appear to impair normal physiological functions until after the first year of life. The latter is, to our knowledge, the first description of an animal genetic model of slowly progressing hydrocephalus. These models are unique in that they avoid the necessity of intracranial injection of sclerotic or hemorrhagic agents to induce the disease. Both the heterozygous and homozygous rat models may be useful for detailed physiological, behavioral and pharmacological studies

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Results

Conclusion