Identification and characterization of novel peroxisomal disorders

Peroxisomes are vital organelles found in virtually every human cell. Defects in peroxisomes may lead to peroxisomal disorders, for example the autosomal recessive Zellweger Spectrum Disorders (ZSDs) which are caused by mutations in different PEX genes. Although many peroxisomal disorders have already been characterized, there is still a number of patients suffering from to date unidentified peroxisomal defects.
In this thesis, we studied such cases to identify the cause of disease, and thus to improve the laboratory diagnosis of future patients. Understanding the underlying disease mechanisms also provides valuable insights into the functioning of peroxisomes and the phenotypical consequences of their defects, which can eventually help to identify potential treatment options.
We discovered
(1) one entirely novel peroxisomal disease, caused by the loss of the peroxisomal protein ACBD5,
(2) one novel genetic disease mechanism causing ZSDs, i.e. the promotion of a mutant PEX6 allele by allelic expression imbalance; a mechanism potentially also involved in other recessive diseases,
(3) the to date mildest form of ZSDs (by identifying the genetic cause of Heimler syndrome as PEX1 or PEX6 defects).
(4) that autophagy inhibition is not an option for curative treatment of peroxisomal diseases.
Finally, this thesis highlights the importance of functional assays to prove the disease-causing character of genetic variants, and to confirm in multiple approaches the effect of potential treatment options.