NHLRC2 in embryonic development, neurodevelopment, and neurodegeneration. Modelling a novel FINCA disease in mouse.

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Leena Palotie auditorium

Topic of the dissertation

NHLRC2 in embryonic development, neurodevelopment, and neurodegeneration. Modelling a novel FINCA disease in mouse.

Doctoral candidate

Master of Science Anniina Hiltunen

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, PEDEGO

Subject of study

Pediatric neurology

Opponent

Professor Mikko Airavaara, University of Helsinki

Custos

Associate Professor Reetta Hinttala, University of Oulu

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Novel FINCA disease and study of disease-causing gene using mouse models.

New disease-causing genes are identified constantly but knowledge on their function is often lacking. Understanding gene function is essential for the development of diagnostics and treatment options. Disease models are important for studying gene function. Here, a novel rare multiorgan disease FINCA was described and function of the previously unknown disease-causing gene NHL repeat containing 2 (NHLRC2) was studied using cell and animal models.

In the first publication a novel severe early infantile-onset disease was characterized. The disease was named FINCA after its main histopathological findings: fibrosis, neurodegeneration, and cerebral angiomatosis. The patients harboured two variants in their NHLRC2 gene. This gene had not been connected to any human disease previously and its function was unknown. The molecular function of NHLRC2 and FINCA disease progression were studied using patient-derived cells, zebra fish model and Nhlrc2 knockout mouse model.

In the second publication a FINCA mouse model was generated by modifying the mouse Nhlrc2 gene to contain one of the patient variants. Unlike Nhlrc2 knockout mouse, which failed early during embryogenesis, FINCA mouse developed normally. This allowed the study of the variant first time in a whole animal. The amount of NHLRC2 in FINCA mouse tissues was significantly decreased but the mice did not develop a severe phenotype. However, altered protein levels were discovered in neurons and brain of FINCA mice.

In the third publication the role of NHLRC2 in embryonic development was studied. The development of Nhlrc2 knockout mice failed during gastrulation, which is the process giving rise to the three germ layers of an embryo.

The results presented in this thesis reveal NHLRC2 as a novel actor in neurodegeneration, fibrosis, and early embryogenesis. In addition, new disease models were generated to study NHLRC2. Since the first publication, FINCA patients have been identified in several countries. In recent years, NHLRC2 has also been associated with neurodevelopmental disorders, inflammation, and cancer. New insight into these more common diseases may arise from studying the pathomechanism of the rare FINCA disease.
Last updated: 27.5.2022