Gene identified in rare, fatal disorder with polycystic kidney/CNS involvement

Caroline Cassels

January 16, 2006

Jan 16, 2006

Rochester, MN - Researchers have discovered a gene involved in causing Meckel-Gruber syndrome (MKS)?a rare and fatal genetic disorder that affects the kidneys as well as the central nervous system (CNS) [ 1 ].

Characterized by bilateral renal cystic dysplasia, CNS malformations, fibrocystic changes in the liver, and polydactyly, MKS affects approximately one in 150¿000 live births. However, there is a reported increased incidence among specific groups, most notably the Finnish population, where it is as high as one in 9000 live births. At greatest risk are consanguineous families. One in four offspring will be afflicted on average in families with two carrier parents.

"This discovery will improve diagnostics in this disorder but, perhaps more important, it will provide greater insight into the pathogenesis of other more common conditions, such as neural-tube defects and polycystic kidney disease [PKD]," lead investigator Dr Peter Harris (Mayo Clinic College of Medicine, Rochester, MN) told renal wire .

Published online January 15, 2006 in Nature Genetics, the study's co-first authors are Dr Ursula M Smith (University of Birmingham Medical School, UK) and Mark Consugar (Mayo Clinic).

In a collaborative effort, the gene was discovered through the combination of the Mayo Clinic's groundbreaking research in the area of PKD genetics, the characterization of a rat model by researchers at Indiana University (Indianapolis) that mimicked PKD but was also associated with the abnormal brain-development characteristic of MKS, and the study of a group of five consanguineous families identified by the University of Birmingham (UK), all of whom had a history of MKS.

After identifying the area in the animal model's genome where the potential error occurred, the researchers ultimately found a single defective gene. Mapping in the five families, all of whom met strict clinical diagnostic criteria for MKS (which included posterior occipital encephalocele, bilateral renal cystic dysplasia, and hepatic developmental defects), highlighted the corresponding area in the human genome and testing the equivalent to the rat gene identified the defect in Meckel-Gruber syndrome type 3 (MKS3).

According to Harris, genetic testing for MKS will be available relatively soon and will help physicians counsel patients with a family history of the disease.

"It will be a small population of patients who will benefit [from testing]. Nevertheless, it will be applicable to families that have a child with Meckel-Gruber syndrome. It will also be of interest to families who have a phenotype that looks like Meckel-Gruber to help determine whether that's really what's going on," said Harris.

The next steps in the team's research, he said, are to examine the protein encoded by the gene to determine its role within the cell and potentially identify other proteins that may interact with it.

"We hope this finding will benefit those at risk of Meckel-Gruber and provide greater understanding of the pathogenesis of PKD, where we've spent most of our time working, and of neural-tube defects, which are beyond the realm of kidney disease, but still extremely important," he said.


  1. Smith UM, Consugar M, Tee LJ, et al. The transmembrane protein meckelin (MKS3 is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 2006; DOI:10.1038/ng1713. Available at: