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More Insight into Sensenbrenner Syndrome
14 March 2011
Dutch Kidney Foundation
Dutch researchers of the Radboud University Medical Center in Nijmegen found a new gene for Sensenbrenner syndrome (Journal of Medical Genetics, 2011 Mar 4). The mutation adds support to the hypothesis that defects in ciliar transport are the cause of the disease. Project leader Dr. Heleen H. Arts is supported by a Kolff Junior Postdoc Grant of the Dutch Kidney Foundation.
Ciliary disease disrupts the cilia, small hairlike organelles that jut out from the cell membrane. Cilia are involved in many important processes, for instance the sensing of fluid streams inside kidney tubules or the registration of light in the light-sensitive cells of the eye. They are antennas that pick up signals that are essential for the cell to react to outside conditions.
The newly found gene codes for IFT43, a protein of the intraflagellar transport complex. This is responsible for the transport of molecules within the cilia. Two genes that were earlier proven to be implicated are also part of the IFT. One of these was found and published last year by the same research group.
According to Dr. Arts, "this third IFT gene strengthens the existing hypothesis that the retrograde transport, from the cilium tip back down to the cell, is affected". She adds that the study is the first to show the IFT defects in cels from Sensenbrenner patients.
The IFT proteins are little molecular trains running along the cilium backbone of microtubules from the cell membrane up and back. They carry the cargo that is necessary for the cilia to function properly.
"We have quite some knowledge about IFT proteins complexes," says Arts. "For instance, the IFT-A complex consists of six proteins and takes care of the retrograde transport. However, the structure of some of the proteins is largely unknown".
When downward transport is compromised the tip of the cilium will swell and cilium function is impaired. "IFT57 molecules get trapped in the cilium tip," explains Arts. "This is one of the proteins that is involved in the upward transport".
There is no cure at hand for ciliary syndromes like Sensenbrenner's. "Understanding the causes is the first step towards therapy," underlines Heleen Arts. "My research is important for improving diagnosis of the disease and for better genetic counseling. I think it is going to take years to develop effective treatment".
Further research is aimed at increasing the knowledge of the genetic background and explaining the mechanisms. Arts: "What exactly happens when the cilium is not functioning optimally? Why is the transport disrupted? Why do these defects result in renal failure? I would like to get an answer to these questions".
For a long time, cilia were viewed as rudimentary cell parts left over by evolution. Today, researchers and doctors realise that faulty cilia are an important cause of serious ailments like Polycystic Kidney Disease and rare syndromes like Sensenbrenner's. Together, these are termed ciliopathies.
Sensenbrenner syndrome is a rare ciliopathy that causes skeletal and ectodermal defects and kidney problems (the ectoderm is the outermost cell layer in the embryo and gives rise to among others skin tissue and nails, nerve tissue, teeth and eye lens). Symptoms are for instance too early closure of skull sutures (craniosynostosis), malformations of the arms and legs or fingers and toes, defects of hair nails and skin, and progressive renal failure. It is a rare condition that is part of a range of overlapping related congenital ciliary syndromes.
Swelling of the cilium tip in a patient with Sensenbrenner syndrome (right) compared to the normal situation (left). Purple marks the cilium base, IFT57 proteins are marked green. © H.H. Arts, Radboud University