Rnaset2-Defizienz: Eine klinisch-experimentelle Betrachtung im Kontext der Typ-1-Interferonopathien
by Carlotta Leonore Seifert née Seifert
Date of Examination:2024-11-28
Date of issue:2024-11-28
Advisor:Prof. Dr. Jutta Gärtner
Referee:Prof. Dr. Jutta Gärtner
Referee:Prof. Dr. Sabine Mihm
Persistent Address:
http://dx.doi.org/10.53846/goediss-10878
Files in this item
Name:Seifert_Carlotta_Dissertation.pdf
Size:4.68Mb
Format:PDF
This file will be freely accessible after 2024-12-26.
Abstract
English
Rnaset2-deficient cystic leukoencephalopathy is a rare congenital disorder caused by a biallelic loss-of-function mutation. This dissertation consists of a clinical and an experimental part on this disease. Clinically, the largest cohort to date (N = 18 patients) has shown that Rnaset2 deficiency leads to a progressive neurological disease. This is accompanied by severe motor and cognitive developmental delays and deficits. The symptoms begin within the first year of life and manifest themselves in varying degrees of severity; in some cases, previously learned skills are lost again. At the time of the last data collection, most of the patients had severe motor impairments. In addition, only two of them were able to speak normally, while almost half were only able to communicate non-verbally. The most common symptoms in the cohort also included spasticity and seizures. In addition, it was shown that the disease often leads to the development of secondary microcephaly and autoimmune phenomena. However, unlike patients with AGS and the Rnaset2-KO mouse, patients with Rnaset2 deficiency showed hardly any symptoms of peripheral inflammatory reactions or organ involvement. Imaging morphology revealed multifocal white matter lesions and temporal, frontal and parietooccipital cysts on MRI as well as calcifications on CT. Experimentally, the protein Siglec-1, which was recently identified as a potential screening parameter for type I interferonoptahias, was measured in the serum of Rnast2-KO mice and affected patients. Furthermore, MEFs from Rnaset2-KO mice were fractionated so that the cytoplasm and nucleus could be analyzed separately by Western blot. This revealed a translocation of the protein IRF9 into the cell nucleus, which takes place as part of the IFN signaling pathway. In this way, an IFN effect could be detected in the MEFs. Analogously, the inflammatory protein Siglec-1 was found to be elevated in the laboratory in blood samples from the KO mouse model, but not in the sample measurement in human blood. Thus, in contrast to AGS, Siglec-1 cannot represent a possible screening marker for Rnaset2 deficiency according to this study. Nevertheless, the clinical overlaps with AGS as a prototype of type I interferonopathies described in the literature were confirmed in many places. The evidence of constitutive IFN release, which was obtained by visualizing the translocation of IRF9 into the cell nucleus using Western blotting, also supports the classification of Rnaset2 deficiency as a type I interferonopathy. This classification is of dual relevance: on the one hand for differential diagnostic consideration in the diagnosis of new patients and on the other hand for the possible future use of drugs that target the type I IFN signaling pathway, as is already the case in AGS.
Keywords: rnaset2 deficiency; IFN; leukencephalopathy; siglec1; CD169; type-I-Interferonopathy
