In-depth investigation of autoinflammatory disorders

Monogenic inherited disorders can cause a variety of disease phenotypes and as a whole pose a serious burden on the healthy system due to the high number of patients affected. In order to administer efficient treatment and provide informed counselling support, the genetic basis of the disorder needs to be identified. While the number of genes causing hereditary disorders is constantly rising, many patients still remain without a genetic diagnosis. The work presented in this thesis add ITPR3 to the disease-causing gene list and describes a total of five variants in six patients from four different kindreds suffering from immunodeficiency, peripheral neuropathy, or a combination of both. ITPR3 encodes the IP3 receptor subtype 3 (IP3R3), an IP3-regulated calcium channel mainly located in the ER membrane. Using primary cells as well as a knockout cell model expressing only the mutated proteins, the presented results demonstrate that the variants cause altered channel activation, ranging from complete loss-of-function to functional hypomorphism to gain-of-function. Therefore, variants in ITPR3 should be considered in patients presenting with immunodeficiency and neuropathy.