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Das CLCN4-Gen kodiert das Protein CIC-4, einen 2Cl-\/H+-Austauscher, der in intrazellul\u00e4ren Kompartimenten in einer Vielzahl von Geweben exprimiert wird, vor allem aber im Gehirn und in der Skelettmuskulatur. Es wird angenommen, dass ClC-4 in den Zellen auf Endosomen und m\u00f6glicherweise im endoplasmatischen Retikulum exprimiert wird und an der Ionenhom\u00f6ostase der Endosomen und dem intrazellul\u00e4ren Transport beteiligt ist. Studien an M\u00e4usen deuten auf eine Rolle von CIC-4 bei der neuronalen Differenzierung hin: Hippocampus-Neuronen von Clcn4-Knockout-M\u00e4usen und Wildtyp-Neuronen, die mit shRNA-vermitteltem Clcn4-Knockdown behandelt wurden, zeigen eine Verringerung der Gesamtzahl der dendritischen Verzweigungen pro Neuron. Die Pathophysiologie der CLCN4-bedingten St\u00f6rungen beim Menschen ist jedoch nur unvollst\u00e4ndig bekannt.<\/p>\n
Das Mutationsspektrum umfasst Frameshift-, Missense- und Splei\u00dfstellenvarianten sowie chromosomale Mikrodeletionen.
Pathogene Missense-Varianten h\u00e4ufen sich in den helikalen Trans- oder Intermembrandom\u00e4nen des Proteins oder in der Cystathionin-\u03b2-Synthase (CBS)-Dom\u00e4ne, von der angenommen wird, dass sie f\u00fcr das Gating des Antiporters wichtig ist. Alle bisher bekannten Missense-Varianten, die sich in diesen Regionen h\u00e4ufen, haben nachweislich eine funktionelle Auswirkung auf elektrophysiologische Studien, wenn sie heterolog in Xenopus laevis-Oozyten exprimiert werden. Alle bisher bekannten betroffenen Frauen haben eine Missense-Variante in CLCN4: heterozygote Tr\u00e4gerinnen in Familien mit vorhergesagten Loss-of-Function-Varianten haben im Wesentlichen einen normalen Ph\u00e4notyp.<\/p>\n
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