Louis Ptacek, MD

Genetics and Biology of Human Nervous System Disorders

My work has focused on identification and characterization of genes that cause normal variations and disorders of the nervous system. One area of particular interest has been in episodic disorders of muscle, heart, and brain. In many cases, these episodic phenomena result from alterations in electrical signaling of cell membranes in these tissues. Initially, by studying a complex group of clinical phenotypes called the periodic paralyses and non-dystrophic myotonias, we began systematically mapping and cloning genes responsible for these phenotypes. These have turned out to be genes that encode ion channels with specificity for sodium, calcium, chloride, and potassium ions. Once identified, it has been possible for us and others to express wild-type and mutant ion channel genes in heterologous expression systems to characterize functional consequences of mutations in the function of these channels. This approach has been very complimentary to site-directed mutagenesis studies that have been done without attention to any particular human disease. These "experiments of nature" focus our attention on discrete regions of the channels and thus can be very informative for structure-function studies. Ongoing work is focused on looking for epistatic interactions between these and other genes, and modeling of the human diseases in other organisms such as mice. The ability to study mutations in vivo will allow us to ask questions that cannot be approached because of the difficulty in obtaining human tissues.

Recently we have identified a gene that causes a rare disorder called Andersen-Tawil syndrome (ATS). The gene accounting for a majority of the families that we've identified is KCNJ2. This gene encodes an inwardly rectifying potassium channel (Kir2.1). Interestingly, ATS is clinically recognized as a triad of periodic paralysis, cardiac arrhythmias, and developmental features affecting the face and limbs. We have done extensive work in characterizing the physiological consequences of these mutations on Kir2.1 currents and also have identified mutations that affect co-assembly and trafficking of these proteins. We've also generated transgenic mice which will allow us to ask questions regarding the role this inwardly rectifying potassium channel in development of cranio-facial and limb structures.

In addition, we are continuing to search for genes causing other episodic phenomena. In a number of cases (epilepsy, movement disorders) the genes that we've identified are not ion channels and represent new windows into understanding other aspects of these episodic phenomena outside of being primary determinants of membrane excitability.

On another front, we became interested in human circadian rhythm genetics upon identifying and characterizing the first human family with a Mendelian variant in their sleep schedule (in collaboration with the laboratory of Ying-Hui Fu). We've gone on to show that these individuals have a familial form of advanced sleep phase syndrome (FASPS). They are normal and healthy but are extreme morning larks. These individuals have a short circadian period that leads them to wake up earlier each day. They ultimately reach an equilibrium where they're waking up so early and going to sleep early enough that they get a strong light impulse to reset their clock for the next day. We've now collected over fifty families with FASPS and are characterizing candidate circadian rhythm genes for variants that cause this phenotype and studying the biochemistry and cell biology of the genetic variants that we're identifying. Furthermore, families that don't have genetic variants in any of the known or predicted candidate genes will provide opportunities to identify novel genetic contributions to human circadian rhythmicity. 

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