Benutzerspezifische Werkzeuge

Summary English

The triple A syndrome is an autosomal recessive disorder, which is characterized by the clinical triad of adrenal insufficiency, alacrima and achalasia of the cardia. Patients present with glucocorticoid deficiency and in some cases with mineralocorticoid and adrenal androgen deficiencies.

A severe dysautonomia points to an impaired function of sympathetic and parasympathetic nerves and to a lack of catecholamine secretion by adrenomedullary chromaffin cells. The syndrome is caused by mutations in the AAAS gene encoding ALADIN, a protein of the nuclear pore complex (NPC). 

Our project focuses on the clarification of the cellular functions of ALADIN and the mechanisms which contribute to the marked adrenal hypotrophy and consecutive insufficiency. We provided evidence that the mistargeting of ALADIN to the NPC results in an increased susceptibility of patient cells against oxidative stress.

We hypothesize that increased oxidative stress leads to degeneration of adrenocortical cells, and that this adrenocortical degeneration also influences the function of the adrenal medulla.

This will be studied using 

1) an ALADIN-depleted human adrenocortical tumour cell line, 

2) primary bovine adrenal cells and 

3) a mouse model generated by crossing Aaas knockout mice with a mice strain with reduced antioxidant functions.

With this project we aim to elucidate the interaction of ALADIN with other adrenal cellular communication systems and its role for normal adrenal function.