Molecular mechanisms of disturbed thermoregulation exemplified by Crisponi syndrome

人类体温调节的机制仍不完全清楚。患有罕见的克里斯波尼综合征的患者在婴儿期出现高热危象，在青春期出现寒冷引起的出汗。在以前的研究中，我们发现CRLF1基因突变是导致这种综合征的原因。最近，我们还在具有“克里波尼样”表型的患者中发现了KLHL7的突变。我们可以证明，Crisponi表型的严重程度取决于单个突变的CRLF1蛋白的分泌能力，患者的冷汗与血浆去甲肾上腺素水平的增加有关。此外，最近，我们发现在CRLF1阴性神经元中，去甲肾上腺素合成的关键酶--多巴胺-β-羟基酶的表达增加。在拟议的项目中，我们将研究KLHL7的缺失是否也会导致中枢去甲肾上腺素合成增加。在这方面，我们将使用神经元KLHL7阴性细胞系，这是由人类诱导的多能干细胞产生的。此外，我们将使用条件基因敲除小鼠模型，在该模型中，Crlf1在中枢神经系统的神经元中被敲除。在这个小鼠模型中，我们将研究CRLF1缺乏对中枢去甲肾上腺素合成、神经元功能和体温调节的影响。该项目不仅将有助于建立一种新的体温调节紊乱的动物模型，而且还将确定治疗Crisponi综合征的新靶点。

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.