Molecular mechanisms of disturbed thermoregulation exemplified by Crisponi syndrome

• Applicant: Professor Dr. Frank Rutsch
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 411699220

Mechanisms of human thermoregulation are still not completely understood. Patients suffering from the rare Crisponi Syndrome develop hyperthermic crises in infancy and cold-induced sweating during adolescence. In previous studies, we identified mutations in the CRLF1 gene as the cause of this syndrome. Recently, we additionally identified mutations in KLHL7 in patients with a "Criponi-like" phenotype. We could demonstrate that the severity of the Crisponi phenotype was dependent on the secretion capacity of the individually mutated CRLF1 protein and that the cold-induced sweating in the patients was associated with an increase of the plasma noradrenaline level. Furthermore, most recently, we showed increased expression of dopamin-beta-hydroxylase, the key enzyme of noradrenalin synthesis, in CRLF1-negative neurons. In the proposed project, we will investigate if also deficiency of KLHL7 leads to increased central noradrenaline synthesis. In this respect, we will employ neuronal KLHL7 negative cell lines, which are generated from human induced pluripotent stem cells. Furthermore, we will use a conditional knockout mouse model, in which Crlf1 is knocked out in neurons of the central nervous system. In this mouse model, we will investigate the consequences of CRLF1 deficiency on central noradrenalin synthesis, neuronal function and thermoregulation. This project will serve not only to establish a novel animal model of disordered thermoregulation, but also to identify new therapeutic targets to treat Crisponi syndrome.

• DFG Programme: Research Grants