Jos Jansen

Chapter 1 10 In 1865, the Czech friar Gregor Mendel conducted his pea-experiments and it was him who first described what is currently known as Mendelian inheritance.(1) With the publication of his ‘Mendelian laws’ he can be considered the founder of modern day genetics. Inborn error of metabolism (IEM) is a term coined in 1908 by Sir Archibald Garrod to describe monogenic diseases that affect metabolism. (2) He was the first to describe alkaptonuria, the first inborn error of metabolism that followed Mendelian laws in 1902.(3) Since then, pivotal discoveries such as DNA’s double helix structure, the first geneticmapping of hereditaryHuntington’s disease, DNA amplification by polymerase chain reaction (PCR) and the mapping of the human genome in the HuGo project were advances that have completely changed the landscape of genetics.(4-7) In 2009, the technology of whole exome sequencing (WES or ‘exome sequencing’) was first published.(8) Exome sequencing is the nucleotide sequencing of all the protein-coding regions in a genome (or the ‘exome’).(9) This method proved especially useful in identifying pathogenic variants in monogenic diseases and quickly after its introduction, its application to inborn errors of metabolism resulted in the identification of novel IEMs.(10-12) Today, exome sequencing has become widely available in patient care and this is one of the reasons that the list of solved Mendelian diseases is growing exponentially, and Congenital Disorders of Glycosylation (CDG), an IEM with defective glycosylation, is no exception. (13) Congenital Disorders of Glycosylation (CDG) Glycosylation Before describing CDG, a brief introduction to glycosylation is beneficial for understanding this specific group of IEM. Glycosylation is the attachment of glycans to newly formed proteins. A glycan is a compound containing different monosaccharides in a predefined arrangement. An overview is shown in Figure 1. Glycans perform several cellular functions such as protein-protein interactions and cell-cell interactions.(14) There are different glycosylation pathways such as N-glycosylation and O-glycosylation. In this thesis, I will focus on N-glycosylation and will refer to this process as ‘glycosylation’. Glycosylation starts on the outer leaflet of the endoplasmatic reticulum (ER) with assembly of the glycan and is then ‘flipped’ by RFT1 to the luminal side. In the lumen, the glycan is further modified and transferred en bloc to the newly formed protein by the oligosaccharyltransferase (OST) complex. The glycoprotein, which is highly mannosylated, is transferred to the Golgi apparatus (or simply ‘Golgi’).