ATP1A3. The ATPases are the “Sisphyean” workhorses of cells, perpetually bound to utilize energy generated by mitochondria to pump ions across cell membranes. This is essential to the maintenance of the intra/extracellular electrochemical gradient. ATP1A3 codes for the α3 subunit of the Na+-K+ ATPase, which utilizes ATP to actively transport sodium out of the cell and potassium into the cell. In the brain, this gradient is critical for cell signaling and for maintaining electrochemical stability, enabling cell excitation and action potential propagation. Both ATP1A3 and one of its counterparts, ATP1A2, are expressed in neurons during embryonal brain development, and ATP1A3 is also thought to contribute to regulation of non-ionic neuronal transporters and receptors. However, whereas ATP1A2 is primarily expressed in glial cells postnatally and into adulthood, ATP1A3 continues to be expressed primarily in neurons, with particular enrichment in excitatory neurons. Here is a brief overview of the clinical spectrum of ATP1A3-related disorders.
A long-awaited answer. Gene discovery in the epilepsies is continuing, and some novel genetic etiologies are quite surprising given that the particular genes had previously been described in a completely different context. One of these examples is TRPM3. In our recent publication, we further define TRPM3 as a gene causative of a variety of neurodevelopmental disorders. Also notably, we find that the anti-seizure medication primidone can be a helpful treatment in individuals with TRPM3. Beyond outlining the TRPM3 spectrum, our publication helped us find a long-awaited diagnosis for one of our research participants, one that took four years to prove. Here is the TRPM3 story. Continue reading
Common variants. In addition to the gradual increase in gene discovery due to exome sequencing, there is a field of human genetics developing in parallel that we have not paid much attention to recently. The role of common genetic variants or Single Nucleotide Polymorphisms (SNP) was initially limited to genome-wide association studies, looking at single variants individually. However, more recently, common variants have been assessed jointly in various diseases, resulting in so-called polygenic scores. In a recent publication in Nature, the polygenic contribution to neurodevelopmental disorders is evaluated. Interestingly, there seems to be a very robust contribution of common variants in neurodevelopmental disorders, even in patients with known de novo variants. Here is a brief discussion on why common variants start getting interesting for the neurogenetics field again. Continue reading