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Researchers discover novel gene and new pathomechanism for Joubert syndrome

Joubert syndrome is a genetic condition that is characterized by a complex brain malformation.

An international team of researchers led by the human geneticist Dr. Hanno Bolz (Institute of Human Genetics, University Hospital of Cologne) and Dr. Bernhard Schermer (head of the Nephrolab Cologne) has identified defects in the KIF7 gene in patients with Joubert syndrome and uncovered a novel mechanism for this disease. The study has been published online in The Journal of Clinical Investigation and will appear in the July print issue.

The team investigated an Egyptian family that tested negative for all known Joubert genes. “Because the parents in this family were related, it was highly suited for identifying a novel gene for Joubert syndrome” says Bolz.

The geneticists localized the disorder to the long arm of chromosome 15 (designation for the new disease gene locus: JBTS12) and subsequently identified mutations in the KIF7 gene in the Egyptian family and in additional patients. KIF7 encodes a ciliary motor protein.

Cilia are antenna-like structures on the cell surface, and many research laboratories worldwide focus on elucidating the functions of this organelle. Cilia are sensory organelles that transmit environmental signals into the cell. An increasing number of genetic diseases have been linked to ciliary dysfunction (the so-called “ciliopathies”).

One patient was found to carry a KIF7 mutation together with two mutations in a known Joubert gene, TMEM67. “This is a phenomenon in ciliopathy genetics that we became more and more aware of over the recent years” explains Dr. Bolz. In 2010, the group has already described similar “oligogenic inheritance” for another ciliopathy, Usher syndrome, also in The Journal of Clinical Investigation. “Besides, KIF7 represents a prime candidate for mono- and oligogenic forms of related ciliopathies, namely Meckel-Gruber, Senior Loken, and Bardet-Biedl syndromes, Leber congenital amaurosis, and nephronophthisis” Bolz adds.

“Chemical substances such as hormones or cytokines bind to ciliary receptors which initiates different activities in the cell” says Dr. Bernhard Schermer. “In the kidney, the urine flow deflects the cilia. Through this, the cells receive informations on flow rate and direction.”

It recently became clear that KIF7 plays a role in Sonic hedgehog (Shh) signaling, a pathway that is crucial for embryonic development. Shh receptors localize exclusively to the cilium. “Our data indicate a function of KIF7 that goes beyond the cilium and hedgehog signaling, to basic cellular processes: Targeted inactivation of KIF7 leads to only mild impairment of cilia formation, but causes dramatic changes of other organelles. As a common basis for these pathologies, we have identified changes in the microtubular cytoskeleton.”

This cytoskeleton regulates important routes of transport through the cell and thereby influences the cell’s shape and orientation. “Our findings indicate a novel pathomechanism for Joubert syndrome that may also be the basis for other ciliopathies” Dr. Schermer concludes.

Besides the two teams from Cologne, researchers from the Ain Shams University in Cairo, the Department of Paediatric Neurology, University Children’s Hospital of Zurich, the Department of Pediatrics, Innsbruck Medical University, the German Cancer Research Center, Heidelberg, des DKFZ in Heidelberg, Zentrum für Kinder- und Jugendmedizin, Klinikum Oldenburg, the Institute of Human Genetics, University Hospital of Schleswig-Holstein, the Department of Radiology and the Department of Anatomy, University of Cologne, contributed to the study.

The study was supported by the Deutsche Forschungsgemeinschaft, the Pro Retina Foundation Germany, Köln Fortune (University Hospital of Cologne), and the Gertrud Kusen-Stiftung.

Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics.
Dafinger C, Liebau MC, Elsayed SM, Hellenbroich Y, Boltshauser E, Korenke GC, Fabretti F, Janecke AR, Ebermann I, Nürnberg G, Nürnberg P, Zentgraf H, Koerber F, Addicks K, Elsobky E, Benzing T, Schermer B, Bolz HJ.
The Journal of Clinical Investigation, 2011.
PD Dr. Hanno Jörn Bolz
Institute of Human Genetics, University Hospital of Cologne, Germany
(currently at the Bioscientia Center for Human Genetics, Ingelheim, Germany)
Phone: +49 6132 781-206
PD Dr. Bernhard Schermer
Nephrologic Research Laboratory
Klinik IV für Innere Medizin
Uniklinik Köln
Telefon: 0221 478-89030
Christoph Wanko
Public Relations Officer
Uniklinik Köln
Telefon: 0221 478-5548

Christoph Wanko | idw
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