Erschienen:
[Erscheinungsort nicht ermittelbar]: Oulun yliopisto, 2022
Sprache:
Englisch
Entstehung:
Hochschulschrift:
Dissertation, Oulun yliopisto, 2022
Anmerkungen:
Beschreibung:
Abstract Rapid development of molecular methods has led to the identification of an increasing number of disease-causing genes and variants, but their molecular function is often unknown. However, understanding their role in normal physiology and in disease is essential for the development of treatment options. In vitro and in vivo disease models are important tools for biomedical research. In vivo models enable the study of physiological processes in the context of a whole animal. Among animal models, mouse is the most used, and has been widely utilised to understand human biology and disease. In the current study, a novel rare multiorgan disease is characterised. Three patients with a previously undescribed early infantile-onset disease were discovered from two unrelated Finnish families. The patients presented with progressive cerebropulmonary and multiorgan symptoms leading to death before 2 years of age. The disease was named FINCA after its main histopathological findings: fibrosis, neurodegeneration, and cerebral angiomatosis. Whole-exome sequencing revealed hetero compound variants in a poorly characterised NHL repeat containing 2 (NHLRC2) gene of the patients. Both variants segregated from healthy heterozygous parents. Patient-derived skin fibroblasts showed a significant decrease in the amount of NHLRC2 protein. Zebrafish and knockout and knockin (KI) mouse models were generated to study the molecular function of the disease-causing gene and the pathogenesis of the disease in vitro and in vivo. Complete loss of Nhlrc2 resulted in early embryonic lethality in mouse revealing an important role for the gene in early embryogenesis. Further analysis showed Nhlrc2 to be essential for completion of gastrulation but not for the viability of embryonic stem cells. The FINCA KI mouse model showed a consistent decrease in NHLRC2 but lacked a severe phenotype. However, studies of the mouse model revealed altered proteins associated with endo- and autolysosomal pathways, and RNA homeostasis in neuronal precursor ...