Efficacy of magnesium chloride in the treatment of Hailey-Hailey disease: from serendipity to evidence on its effect on intracellular Ca2+ homeostasis

Background: Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare autosomal dominant inherited intraepidermal blistering genodermatosis. Mutations in the ATP2C1 gene encoding for the Golgi secretory pathway Ca2+/Mn2+-ATPasi protein 1 (SPCA1) affect the processing of desmosomal components and the epidermal suprabasal cell-cell adhesion by deregulating the keratinocyte cytosolic Ca2+ concentration. We report the unexpected, dramatic and persistent clinical improvement of the skin lesions of a patient affected with long standing HHD with daily intake of a solution containing magnesium chloride hexahydrate (MgCl2). Methods: We investigated the effect of MgCl2 on the intracellular Ca2+ homeostasis and on the activity of particular Ca2+-effectors in HeLa cells transfected with chimeric aequorins (cytAEQ, mtAEQ, erAEQ and GoAEQ) targeted to different subcellular compartments (cytosol, mitochondria, endoplasmic reticulum and Golgi, respectively). Results: Experimental investigations on HeLa cells showed the effect of MgCl2 on the function of Ca2+-extrusor systems, resulting in increased cytosolic and mitochondrial Ca2+ levels, without altering the mechanisms of intraluminal Ca2+-filling and Ca2+-release of stores. Conclusions: Based on our clinical observation and experimental results, it can be hypothesized that MgCl2 could act as an inhibitor of the Ca2+-extruding activity in keratinocytes favoring intracellular Ca2+-disponibility and Ca2+-dependent mechanisms in desmosome assembly. This may represent the molecular basis of the good response of the HHD clinical features with MgCl2 solution in the patient described.