I have a new paper out, published in Neurology Genetics, called “CDKL5 variants: Improving our understanding of a rare neurological condition.” This is a study of all the genetic variants we see in the CDKL5 gene, in both patients with CDKL5 deficiency and in the general population, and was carried out during my year being funded by CDKL5 UK. Although I say ‘my’ paper, this was a team effort (like all scientific efforts) and I’m extremely grateful to all the co-authors who supplied me with vital information and advice. The paper is open-access, so anyone can download it from this link: http://ng.neurology.org/content/3/6/e200.
I’ve been very interested in recent large-scale studies in which thousands of people in the general population had their DNA and RNA sequenced. If you look at specific genes and compare these populations to patients with mutations in CDKL5 you can gain insights into which parts of the gene (and protein) are important for CDKL5 function, and how best to target genetic therapies. That’s what I did in this new study, with CDKL5.
Certain types of variants (missense variants, where a single amino acid is changed in the CDKL5 protein) cluster in the catalytic domain of CDKL5. This means that the catalytic domain is almost certainly the most important domain in CDKL5 in terms of its function. We can’t rule out the rest of the protein (the catalytic domain only constitutes the first third of the protein), but we don’t yet know what function the rest of the protein performs. Several labs, funded by the Loulou foundation, will hopefully shed some light on this. We also found more evidence that variants in the last three exons of CDKL5 (exons are the building blocks of the gene) are unlikely to be disease-causing, adding weight to a 2014 study. This tells us something about how important the different protein isoforms are to the pathogenicity of CDKL5 (isoforms are the different versions of CDKL5 protein produced in the cell). This information is helping to inform our lab and other labs about how best to develop therapies for CDKL5 deficiency.
If you have any questions about the paper, please get in touch (firstname.lastname@example.org). I’ll follow up with another blog in January about the recent CDKL5 Forum conference. Hope you have all had a good Christmas and are looking forward to 2018.