Charakterisierung des Proteins Dok-7 and der neuromuskulären Endplatte
Zusammenfassung der Projektergebnisse
Congenital myasthenic syndromes (CMS) are a group of inherited disorders where failure of signal transmission between nerve and muscle leads to skeletal muscle weakness. Weakness may affect different muscle groups, generally sets in at birth or in early childhood and is enhanced by physical exercise. A relevant proportion of CMS are caused by mutation in a novel gene called DOK7 (“downstream of kinase 7” or “docking protein 7”) firstly described in 2006. Disease features of DOK7-related CMS are rather atypical and might be very severe. At the time of the start of my project no efficient treatment was available, as DOK7 patients do not show a good response to the conventional CMS treatment with acetylcholinesterase inhibitors. We identified additional patients with DOK7 mutations and a successful pilot longterm treatment study with the drug ephedrine was performed on some of our DOK7 patients. At the molecular level, disease mechanisms of DOK7 mutations – in contrast to mutations in other CMS target genes - rather affect neuromuscular junction (NMJ) structure than the signal transmission process itself. Although the Dok-7 protein has previously been studied in cell culture, crucial questions regarding the pathogenic mechanisms of DOK7 mutations in CMS remain open, as the in vivo role of Dok-7 at the innervated endplate region is still not well understood. The Dok-7 knockout mouse is neonatally lethal, making it difficult to study Dok-7 function in a mammalian model. Considering the effect of DOK7 mutations on NMJ structure, it seems likely that Dok-7 has a very complex role during NMJ development and maturation. To address this and to circumvent the difficulties of the mouse model, I investigated the in vivo function of Dok-7 in zebrafish. I characterised the zebrafish ortholog of Dok-7 and analysed its involvement at the different stages of NMJ development. In zebrafish, deficiency of Dok-7 leads to impaired motility in zebrafish embryos and larvae. I showed that zebrafish Dok-7 is essential for the first step of NMJ formation before the motor neuron reaches its target muscle fibre. Dok-7 is not essential for later steps, as NMJs do form, but it seems to be relevant for determining NMJ size. Furthermore, I provide evidence that - in addition to its function at the NMJ - zebrafish Dok-7 might be involved in maintaining muscle fibre structure. This finding uncovers a previously unknown role for Dok-7 and might increase our understanding of unusual clinical and molecular findings in patients. Following the DFG scholarship I have been awarded a Faculty Research Fellowship by the Faculty of Medical Sciences, Newcastle University, which will allow me to pursue the project further.
Projektbezogene Publikationen (Auswahl)
- Clinical and molecular genetic findings in 22 COLQ- mutant CMS patients. Brain, 2008; 131: 747- 59
Müller JS, Mihaylova V, Vilchez JJ, Salih MA, Kabiraj MM, D’Amico A, Bertini E, Wölfle J, Schreiner F, Kurlemann G, Milic Rasic V, Siskova D, Colomer J, Herczegfalvi A, Fabriciova K, Weschke B, Scola R, Hoellen F, Schara U, Abicht A, Lochmüller H
- Late onset in dysferlinopathy widens the clinical spectrum. Neuromuscul Disord., 2008; 18(4): 288-90
Klinge L, Dean AF, Kress W, Dixon P, Charlton R, Müller JS, Anderson LV, Straub V, Barresi R, Lochmüller H, Bushby K
- The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology, 2008; 71(24): 1967-72
Richard P, Gaudon K, Haddad H, Ammar AB, Genin E, Bauché S, Paturneau-Jouas M, Müller JS, Lochmüller H, Grid D, Hamri A, Nouioua S, Tazir M, Mayer M, Desnuelle C, Barois A, Chabrol B, Pouget J, Koenig J, Gouider-Khouja N, Hentati F, Eymard B, Hantaï D
