Congenital brain malformation caused by mutations in novel disease genes

Nearly all human cells have primary cilia, whose function is to sense the external environment and co-ordinate the appropriate cell responses. Defects in ciliary function cause disorders called ciliopathies, which may affect nearly any organ. The brain malformations described in ciliopathies are manifold, comprising mid-hindbrain malformation, migration disorders or the absence of major brain structures. 

In our project, we study patients with brain malformations compatible with primary ciliary deficiency. We analyze all known genes in whole exome sequencing (WES-data) from the patients.

When candidate disease causing mutations are detected in genes not previously associated with disease (putative “novel disease genes”), we perform pathogenicity validation by transient gene knock down and ectopic over expression experiments in vitro and in vivo. We use patient fibroblasts to characterize structural and functional cilia defects caused by the mutations detected. Studies of strong candidate genes are performed in CRISPR/Cas9 mutated zebrafish larvae focusing primarily on brain phenotypes.

This multi-disciplinary approach allow us to identify novel disease mechanisms causing congenital brain malformations, and to study how the ciliary defects cause the clinical phenotypes.

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Contributions by the student

The student will initiate experiments to analyze one promising novel candidate disease gene already identified by comparison of WES-data from patients and parents. The student will perform in silico studies to predict pathogenicity and assess effects on protein structure.

The molecular consequences of the variant will be studied in vitro using fibroblasts from patients (serum-starvation of the fibroblasts induces cilia development).

Manipulation of candidate gene expression will be obtained by RNAi and ectopic expression from cDNA constructs. Gene expression levels in transfected cells will be measured by qRT PCR.

Qualitative and quantitative immunofluorescence (IF) microscopy assays will be used to assess changes in cilia number and structure (length of the cilia, location and abundance of ciliary proteins).

Cilia function may be explored using protein extracts (total protein, nuclear or cytoplasmic extracts). These extracts will be analyzed by western blot assays to quantify the levels of the proteins of interest in patient cells, and to assess activation of the main signal transduction pathways downstream of the cilia.

Research environment

The project is carried out within Prof. E. Frengen’s research group at Department of Medical Genetics, University of Oslo/Oslo Univerity Hospital. The student will be supervised by Frengen and Dr. D. Misceo (co-PI).

Information about Frengen’s research group:

For more information, contact Eirik Frengen, at or +47 95882233


Publisert 1. okt. 2020 15:47 - Sist endret 1. okt. 2020 16:26


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