Interactions of silent Kv subunits and their role in DRG neurons.

PhD in Biochemistry & biotechnology

Voltage-gated K⁺ channels are widely expressed in native tissues. Four α-subunits tetramerize in a fully assembled K⁺ channel. Based on homology, voltage-gated K⁺ channels are subdivided into several (sub)families. De Kv family consist of 8 subfamilies.
Members of the Kv1-Kv4 subfamilies produce functional channels in a homotetrameric configuration. Through assembly into heterotetrameric channels, the heterogeneity of these subfamilies increased. Only members of the same subfamily can form heterotetramers. The Kv2 subfamily only consists of two members, Kv2.1 and Kv2.2. Both channels and their heteromeric complexes display similar currents resulting in a small functional diversity of the subfamily. However, the heterogeneity of Kv2.x is increased through tetramerization with subunits of the Kv5-Kv6, Kv8-Kv9 subfamilies. These subunits are designated silent Kv subunits as these do not produce functional channels in a homotetrameric conformation. At present, every silent Kv subunit is able to associate with the Kv2.x subunits into a functional heterotetrameric channel resulting in biophysical properties that are altered compared to homotetrameric Kv2 channels. Furthermore, these silent Kv subunits show a more specific expression pattern while Kv2 subunits are widely expressed in neuronal tissue where they underlie the delayed rectifier current. Using electrophysiological, immunocytochemical, FRET and co-IP experiments the association between the Kv2 and silent Kv subunits is investigated. Furthermore, the presence and functional effects of the silent Kv subunits in DRG neurons is examined.

Promotor(s)

Identification of susceptibility genes for psychiatric disorders through a functional genomics approach.

PhD in Biochemistry & biotechnology

Bipolar (BP) disorder and schizophrenia (SZ) are among the most common brain diseases worldwide and result in high social and economical costs in terms of morbidity as well as mortality. Both complex genetic and environmental factors play an important role in their development.

Our aim is to understand the different mechanisms that underlie these psychiatric disorders. This will be realized by examining three hypotheses, all with the primary aim to identify positional and functional candidate genes for BP disorder and/or SZ.

Hypothesis 1: Identification of positional candidate genes on chromosome 6.

We found a strong indication for linkage on chromosome 6q23-q24 in nine northern Swedish multigenerational families. This region will be fine-mapped by using SNP based genotyping methods, followed by a SNP based association study in large patient/control populations.

Hypothesis 2: Importance of copy number variations (CNVs) on the susceptibility for BP and SZ.

The literature strongly indicates that CNVs might be responsible for complex disorders such as BP disorder and SZ. The potential instable regions will be analysed in our association populations by using an in house developed method (Multiplex Amplicon Quantification – MAQ). By doing this we’ll gain insight in the significance of genomic instability as the underlying cause of BP disorder and SZ.

Hypothesis 3: Post-transcriptional modifications as a cause of BP disorder and SZ.

It is assumed that certain mechanisms, like gene regulation, are responsible for complex disorders. A-to-I RNA editing by “ Adenosine Deaminases Acting on RNA” (ADAR) is a form of post-transcriptional modification, which is already described for mRNAs coding for the serotonin receptor 5-HTR2C and for several glutamate receptors. The different ADAR- and target-genes that are possibly related to BP disorder and SZ will be subjected to an association study and mutation analysis.

Promotor(s)

Prof. Dr. Ir. Jurgen Del-Favero

Prof. Rolf Adolfsson, MD

Identification of molecular partners interacting with mutant genes associated with Charcot-Marie-Tooth neuropathies

PhD in Biomedical sciences

Inherited peripheral neuropathies comprise a very complex and genetically diverse group of disorders. Charcot-Marie-Tooth (CMT) is the most common type of peripheral neuropathy and is clinically characterized by weakness and wasting of distal muscles such as foot and hands. There are currently 35 described genes related to these disorders, and for some of these the pathomechanism is relatively well defined due to the participation in processes essential for the development and maintenance of the peripheral nerves such as myelin and neurofilament formation. However, in the last years, some CMT disease associated genes were identified but their pathomechanism is not clear, either because they are ubiquitously expressed or participate in processes that are common to several types of cells (i.e. aminoacylation and protein folding). Among them figures YARS, a tyrosil-tRNA synthetase and two small heat shock proteins HSPB1 and HSPB8.

To get a better picture of the possible pathomechanism involved in these inherited disorders, we intend to compare the complexes formed with the wild type versus the mutant form of these proteins focusing in gain or loss of interaction partners. Immunoprecipitation is the most used methodology to identify protein complexes and a modification of this technique, called Tandem Affinity Purification (TAP), has been used quite extensively in the last few years due to its lower background and fidelity increase.

Promotor(s)

Vincent Timmerman
Sophie Janssens