Investigation of molecular interplay between Nphp2- and Bbs4 and its role in ciliogenesis, cilia maintenance and developmental signalling pathways
Final Report Abstract
Against our expectations I could not find evidence for any egnetic epistasis between BBS4 and Inversin. Although this is a „negative“ finding this stil adds to our knowledge about ciliopathies especially under the recently evolving theories about „mutational load“ in ciliopathies. My work has revealed some new aspects regarding the BBS4 kidney phneotype in mice (late, low penetrance, histological picture rather ressembling a glomerulocystic phneotype then a nephronophthisis phenotype). I was not able to improve kidney function in these mice using rapamycin, a substance currently used in clinical trials for polycystic kidney diseases. The latter inspired me to persue further substance screening for therapeutics influencing progression of cystic kidney disease using a highthroughput zebrafish system. I obtained positive reuslts from this screen and I am currently finishing this project with a in vivo study using cystic mouse models. I was further involved in generated a zebrafish modes for a newly identified gene (PF22, DNAAF3) causing PCD and a new gene for Jeune Syndrome (efr3a). I feel I have achieved my aims for the DFG Fellowship regarding acuisition of new experimental techniques. I am now very confident in zebrafish Morpholino induced gene knockdown including phenotype assessment, a tool that is particularily useful in genetic and translational therapy research. Further I have gained experience and knowledge in the area of knockout mouse models as well as gene discovery in human genetics . I feel I now have a stable background knowledge in develpmental biology in addition to my cell biology bakground from previous research experiences.
Publications
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Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am J Hum Genet. 2009 Dec;85(6):883-9
Loges NT, Olbrich H, Becker-Heck A, Häffner K, Heer A, Reinhard C, Schmidts M, Kispert A, Zariwala MA, Leigh MW, Knowles MR, Zentgraf H, Seithe H, Nürnberg G, Nürnberg P, Reinhardt R, Omran H
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CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet. 2011 Jan;43(1):72-8. Epub 2010 Dec 5
Merveille AC, Davis EE, Becker-Heck A, Legendre M, Amirav I, Bataille G, Belmont J, Beydon N, Billen F, Clément A, Clercx C, Coste A, Crosbie R, de Blic J, Deleuze S, Duquesnoy P, Escalier D, Escudier E, Fliegauf M, Horvath J, Hill K, Jorissen M, Just J, Kispert A, Lathrop M, Loges NT, Marthin JK, Momozawa Y, Montantin G, Nielsen KG, Olbrich H, Papon JF, Rayet I, Roger G, Schmidts M, Tenreiro H, Towbin JA, Zelenika D, Zentgraf H, Georges M, Lequarré AS, Katsanis N, Omran H, Amselem S
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D-lactic acidosis: "right-left disorientation" in laboratory testing: acute encephalopathy in a child with carbohydrate malabsorption syndrome. J Pediatr Gastroenterol Nutr. 2010 Jan;50(1):106-7
Grünert S, Schmidts M, Kenzel S, Sass JO, Greiner P, Pohl M, Hentschel R
