Identification of pathomechanisms

For many neuromuscular diseases, the genetic cause is known, and the challenge is then to translate these gene discoveries into patient-tailored treatments. To achieve this, disease-relevant models are essential to support characterization of the disease, unravel the pathogenic mechanisms, identify new therapeutic targets for intervention, and perform preclinical testing where potential therapeutics/targets are identified. The full elucidation of pathomechanisms is crucial not only to fully understand the molecular causes of the diseases but also to define starting points for testing of potential therapeutic interventions. To this end, our lab generates animal models and makes use of patient-derived material, often in close collaboration with other international research groups, using techniques including cell biology approaches, functional studies, genomics, transcriptomics, proteomics and immunological techniques such as immunofluorescence studies. The development of animal models (mouse and zebrafish) for a variety of neuromuscular diseases has enabled us to study the phenotypic consequences of gene knock-down and associated pathomechanisms in vivo, which not only allows validation of gene discoveries but also provides insights towards ways of correcting the defect and thus towards therapeutic targets.


Relevant publications

Donkervoort, S, Mohassel, P, Laugwitz, L, Zaki, MS, Kamsteeg, EJ, Maroofian, R et al.. Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome. Am J Med Genet A. 2020.182 (10)2272-2283 PMID:32776697

Töpf, A, Oktay, Y, Balaraju, S, Yilmaz, E, Sonmezler, E, Yis, U et al.. Severe neurodevelopmental disease caused by a homozygous TLK2 variant. Eur J Hum Genet. 2020.28 (3)383-387 PMID:31558842

McMacken, GM, Spendiff, S, Whittaker, RG, O'Connor, E, Howarth, RM, Boczonadi, V et al.. Salbutamol modifies the neuromuscular junction in a mouse model of ColQ myasthenic syndrome. Hum Mol Genet. 2019.28 (14)2339-2351 PMID:31220253

Cipriani, S, Phan, V, Médard, JJ, Horvath, R, Lochmüller, H, Chrast, R et al.. Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C. Int J Mol Sci. 2018.19 (12) PMID:30562927

Issop, Y, Hathazi, D, Khan, MM, Rudolf, R, Weis, J, Spendiff, S et al.. GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice. Hum Mol Genet. 2018.27 (18)3218-3232 PMID:29905857

O'Connor, E, Phan, V, Cordts, I, Cairns, G, Hettwer, S, Cox, D et al.. MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Hum Mol Genet. 2018.27 (8)1434-1446 PMID:29462312

O'Connor, E, Töpf, A, Zahedi, RP, Spendiff, S, Cox, D, Roos, A et al.. Clinical and research strategies for limb-girdle congenital myasthenic syndromes. Ann N Y Acad Sci. 2018.1412 (1)102-112 PMID:29315608

Nicole, S, Azuma, Y, Bauché, S, Eymard, B, Lochmüller, H, Slater, C et al.. Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions. J Neuromuscul Dis. .4 (4)269-284 PMID:29125502

Unger, A, Beckendorf, L, Böhme, P, Kley, R, von Frieling-Salewsky, M, Lochmüller, H et al.. Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function. Acta Neuropathol Commun. 2017.5 (1)72 PMID:28915917

Klymiuk, N, Blutke, A, Graf, A, Krause, S, Burkhardt, K, Wuensch, A et al.. Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle. Hum Mol Genet. 2013.22 (21)4368-82 PMID:23784375