Role of Aquaporin-4 isoform mutations in megalencephalic leukoencephalopathy with subcortical cysts

Maintaining brain volume homeostasis is crucial as any significant change in brain volume can lead to serious health problems. For instance, an increase in brain volume can cause increased intracranial pressure which can lead to headaches, vomiting, vision problems, mental changes and in severe cases can be life-threatening. On the other hand, a decrease in brain volume can be a sign of conditions like dementia or Alzheimer’s disease. Therefore, maintaining brain volume homeostasis is essential for overall health and well-being. Megalencephalic leukoencephalopathy with subcortical cysts-4 (MLC4) is an autosomal recessive neurologic disorder characterized by macrocephaly in infancy. In a recent study, a homozygous missense mutation in the AQP4 gene (A215T) was identified in two siblings born of consanguineous parents, with remitting MLC4. The AQP4 gene is the predominant water channel in the brain and has an important role in brain volume homeostasis. However, AQP4 is expressed in brain astrocytes in different isoforms which have distinct properties with respect to water transport, sensitivity to osmotic stimuli and relative distribution in parenchyma and perivascular astrocyte domains. The objective of the proposed research is to establish the effect of the mutation in each specific AQP4 isoform and determine whether the reported mutation is the underlaying cause of MLC4. This study is anticipated to enhance our understanding to MELP's cellular mechanisms and provide fundamental information for a pharmacological approach.