Novel insights into the pathomechanisms of congenital myasthenic syndromes (CMS)

• Applicant: Privatdozentin Dr. Angela Abicht
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2007 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 56603828

The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle and to induce muscle contraction. Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders of the NMJ that impair neuromuscular transmission. Causal defects in presynaptic nerve terminal, synaptic cleft, and postsynaptic apparatus have been identified. Biochemical studies of CMS-causing mutations allow a better understanding of the function and interaction partners of the affected proteins and offer a more detailed view on the organization and maintenance of the NMJ structures. Within the last years, molecular genetic analysis in our collective of more than 400 CMS patients of various ethnic origins led to the identification and characterization of numerous disease-causing mutations. Recently, we and others described mutations in a novel CMS gene (DOK7) gene leading to a characteristic clinical phenotype. Functional studies of DOK7 mutations will be carried out in vitro to determine the pathogenicity of mutations and to further understand the molecular mechanisms of synaptic dysfunction caused by this novel described CMS gene. In addition, functional studies of CHRND mutations and mutated constructs will be carried out in vitro to define in detail the differential role of AChR subunits and their structures in the interaction process with rapsyn. In conclusion, we expect that our project will add more exciting details to the knowledge about CMS-causing genes, the neuromuscular transmission, and the organization and maintenance of NMJ structures. Clinically, a precise molecular classification of CMS is of paramount importance for the diagnosis, counseling and therapy of a patient.

• DFG Programme: Research Grants