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A mouse model for Meckel syndrome type 3
Susan A Cook1, Gayle B Collin, Roderick T Bronson
1The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Abstract:
Meckel-Gruber syndrome type 3 (MKS3; OMIM 607361) is a severe autosomal recessive disorder characterized by bilateral polycystic kidney disease. Other malformations associated with MKS3 include cystic changes in the liver, polydactyly, and brain abnormalities (occipital encephalocele, hydrocephalus, and Dandy Walker-type cerebellar anomalies). The disorder is hypothesized to be caused by defects in primary cilia. In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium. Here, we describe a spontaneous deletion of the mouse ortholog, Tmem67, which results in polycystic kidney disease and death by 3 wk after birth. Hydrocephalus also occurs in some mutants. We verified the mutated gene by transgenic rescue and characterized the phenotype with microcomputed tomography, histology, scanning electron microscopy, and immunohistochemistry. This mutant provides a mouse model for MKS3 and adds to the growing set of mammalian models essential for studying the role of the primary cilium in kidney function.
Insights
A new mouse model with a Tmem67 gene deletion mimics Meckel-Gruber syndrome type 3 (MKS3), exhibiting polycystic kidney disease and hydrocephalus. This discovery aids research into primary cilia
Area of Science:
- Genetics
- Developmental Biology
- Nephrology
Background:
- Meckel-Gruber syndrome type 3 (MKS3) is a severe autosomal recessive disorder.
- MKS3 is characterized by polycystic kidney disease, liver cysts, polydactyly, and brain abnormalities.
- Defects in primary cilia are hypothesized to cause MKS3.
Purpose of the Study:
- To describe a novel mouse model for Meckel-Gruber syndrome type 3.
- To investigate the role of the Tmem67 gene in kidney development and primary cilia function.
Main Methods:
- Spontaneous deletion of the mouse ortholog Tmem67.
- Phenotypic characterization using microcomputed tomography, histology, scanning electron microscopy, and immunohistochemistry.
- Transgenic rescue to verify the mutated gene.
Main Results:
- The Tmem67 deletion mouse model exhibits polycystic kidney disease and premature death.
- Hydrocephalus was observed in some Tmem67 mutant mice.
- The study confirmed Tmem67 as the mutated gene responsible for the observed phenotype.
Conclusions:
- The Tmem67 deletion mouse provides a valuable model for studying MKS3.
- This model will advance understanding of the primary cilium's role in kidney development and disease.
- Further research can explore therapeutic strategies for MKS3 and related ciliopathies.
