Researchers discover novel gene and new pathomechanism for Joubert syndrome

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.

Publication:
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.
doi:10.1172/JCI43639
http://www.jci.org/articles/view/43639
Contact:
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
E-Mail: hanno.bolz@uk-koeln.de
PD Dr. Bernhard Schermer
Nephrologic Research Laboratory
Klinik IV für Innere Medizin
Uniklinik Köln
Telefon: 0221 478-89030
E-Mail: bernhard.schermer@uk-koeln.de
Christoph Wanko
Public Relations Officer
Uniklinik Köln
Telefon: 0221 478-5548
E-Mail: christoph.wanko@uk-koeln.de

Media Contact

Christoph Wanko idw

More Information:

http://www.uk-koeln.de

All latest news from the category: Life Sciences and Chemistry

Articles and reports from the Life Sciences and chemistry area deal with applied and basic research into modern biology, chemistry and human medicine.

Valuable information can be found on a range of life sciences fields including bacteriology, biochemistry, bionics, bioinformatics, biophysics, biotechnology, genetics, geobotany, human biology, marine biology, microbiology, molecular biology, cellular biology, zoology, bioinorganic chemistry, microchemistry and environmental chemistry.

Back to home

Comments (0)

Write a comment

Newest articles

Lighting up the future

New multidisciplinary research from the University of St Andrews could lead to more efficient televisions, computer screens and lighting. Researchers at the Organic Semiconductor Centre in the School of Physics and…

Researchers crack sugarcane’s complex genetic code

Sweet success: Scientists created a highly accurate reference genome for one of the most important modern crops and found a rare example of how genes confer disease resistance in plants….

Evolution of the most powerful ocean current on Earth

The Antarctic Circumpolar Current plays an important part in global overturning circulation, the exchange of heat and CO2 between the ocean and atmosphere, and the stability of Antarctica’s ice sheets….

Partners & Sponsors