Pathomechanisms of human diseases

Monogenetic diseases provide a direct link between a change in protein function to cell and organ dysfunction. Studying monogenetic diseases often permits identification of cellular roles of ion channels. Moreover, disease-causing mutations usually affect important functions of the affected proteins, and analysis of the functional consequences of such mutations thus provides novel insights into the molecular determinants of protein functions.Monogenetic diseases can be studied at the molecular, cellular and organ level in knock-in animals of the respective gene. Understanding the pathomechanisms of monogenetic diseases permit prediction of novel therapeutic approaches that can be tested in cell and organ preparations of these animals.In the past, we have studied monogenetic disease affecting muscle excitability (1-6), renal salt secretion (7), inner ear function (8,9), aldosteronism (10,11) as well as epilepsy (12,13), episodic ataxia (14,15) and migraine.

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5. Weinberger, S. et al. Disease-causing mutations C277R and C277Y modify gating of human ClC-1 chloride channels in myotonia congenita. J Physiol 590, 3449-3464, doi:10.1113/jphysiol.2012.232785 (2012).
6. Ronstedt, K. et al. Impaired surface membrane insertion of homo- and heterodimeric human muscle chloride channels carrying amino-terminal myotonia-causing mutations. Scientific reports 5, 15382, doi:10.1038/srep15382 (2015).
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8. Riazuddin, S. et al. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am.J.Hum.Genet. 85, 273-280 (2009).
9. Tan, H., Bungert-Plumke, S., Fahlke, C. & Stolting, G. Reduced Membrane Insertion of CLC-K by V33L Barttin Results in Loss of Hearing, but Leaves Kidney Function Intact. Front Physiol 8, 269, doi:10.3389/fphys.2017.00269 (2017).
10. Scholl, U. I. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 45, 1050-1054, doi:10.1038/ng.2695 (2013).
11. Scholl, U. I. et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. eLife 4, doi:10.7554/eLife.06315 (2015).
12. Saint-Martin, C. et al. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Hum.Mutat. 30, 397-405 (2009).
13. Stolting, G. et al. Regulation of ClC-2 gating by intracellular ATP. Pflugers Arch 465, 1423-1437, doi:10.1007/s00424-013-1286-0 (2013).
14. Winter, N., Kovermann, P. & Fahlke, C. A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. Brain 135, 3416-3425, doi:10.1093/brain/aws255 (2012).
15. Hotzy, J., Schneider, N., Kovermann, P. & Fahlke, C. Mutating a Conserved Proline Residue within the Trimerization Domain Modifies Na+ Binding to Excitatory Amino Acid Transporters and Associated Conformational Changes. J Biol Chem 288, 36492-36501, doi:10.1074/jbc.M113.489385 (2013).