Louis Ptacek
Neurology
Adjunct Assistant Professor

Contribution to Society

Identification of genes that cause neurogenetic disorders makes genetic diagnosis possible for people who have inherited mutant alleles. While such possibilities will never replace clinical evaluation, they represent an important potential aid to physicians who care for patients with these types of disorders. The characterization of mutations in the various genes involved in neurogenetic disorders will allow precise categorization of patients in therapeutic trials and make such trials more informative. Furthermore, an understanding of the molecular basis of such diseases may lead to more rational approaches to development of new medications.

In addition to these clinical benefits, study of the molecular abnormalities leading to these disorders will help us to understand the physiology of normal and abnormal muscle membranes. Furthermore, understanding of perturbations of gene function may ultimately lead to a better understanding of the molecular basis of other more common neurologic disorders, including those that are not monogenetic mendelian traits. Examples of complex genetic traits include epilepsy, migraine, and multiple sclerosis.

Research Summary

Work in our lab involves study of genetic disorders of the nervous system. We are interested in identifying genes that cause human disease and in studying mutant and normal products of these genes to understand the role of these proteins in health and in disease. Through such studies we hope to understand the molecular basis of disorders of the nervous system, as well as to use such information (ultimately) in devising new therapies for patients.

Three primary areas of focus are being pursued:

1. Paroxysmal disorders of the nervous system/modulation of membrane excitability. A large number of disorders of the nervous system are known in which episodic attacks occur in otherwise normal people without warning. This group of disorders includes the periodic paralyses, episodic ataxia, migraine headaches, and epilepsy. Early work in the laboratory was aimed at understanding the pathogenesis of the disorders of muscle (the periodic paralyses), in which attacks of weakness come on intermittently in otherwise normal people. Study of such patients and their families led us to identify two genes that cause at least five distinct muscular dystrophies with periodic paralysis. Subsequently, we have made both wild type and mutant constructs and expressed them in vitro in an attempt to understand the molecular basis for the disease in these patients. Finally, this work has led to a therapeutic trial in patients with these diseases in the hopes of using such information to make an impact in treatment of patients.

   This work has now extended to a number of different episodic neurologic disorders, including migraine headache and epilepsy. We are currently pursuing two genes that cause epilepsy (1 in mouse and 1 in human). Again, this work is directed at understanding the molecular basis of these diseases, and toward biological study of these genes and the proteins they encode. Molecules that are important for regulating membrane excitability in both muscle and neurons include ionic transporters and exchangers, voltage and ligand gated ion channels, metabatropic receptors, as well as the large group of molecules that modulate the expression of these proteins.

2. A second area of focus in the laboratory is in a group of disorders that involve hereditary degeneration of the nervous system. We have mapped four genes that cause hereditary neurodegeneration. We are in the process of cloning these genes, which will then allow us to studying the wild type and mutant proteins in vitro. Such work may lead ultimately to biologic study of genes important to the cyto-architecture of neurons, the regulation of cell development and maintenance, and to apoptosis in the nervous system.

3. Finally, we have identified families with the first recognized Mendelian circadian rhythm disorder. These individuals have advance of their sleep phase so that they fall asleep early in the evening and awake very early in the morning. We are in the process of collecting several families with this trait and will map and clone the gene in the hope of gaining some new insight into circadian rhythms in humans.

Recent Publications

Plaster, NM, Tawil R, Tristani-Firouze M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony S, Wolfe G, Fu Y-H, Ptácek LJ (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's Syndrome. Cell 105:511-519

Skradski S, Clark A, Jiang H, White S, Fu Y-H, Ptácek LJ (2001) A novel gene causing an audiogenic mouse epilepsy. Neuron In press

Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu Y-H (2001) An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep-Phase Syndrome. Science 291:1040-1043

Abbott GW, Butler MH, Bendahhou S, Dalakas M, Ptácek LJ, Goldstein L (2001) Mirp2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104:217-231

Bendahhou S, Cummins T, Hahn A, Langlois S, Waxman SG, Ptácek LJ (2000) A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation. Journal of Clinical Investigation 106:431-438

Coffeen CM, McKenna CE, Koeppen AH, Plaster NM, Maragakis N, Mihalopoulos J, Schwankhaus JD, Flanigan KM, Gregg RG, Ptácek LJ, Fu YH (2000) Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. Human Molecular Genetics 9:787-793

Zhang J, Sanguinetti MC, Kwiecinski H, Ptácek LJ (2000) Characterization of functional consequences of ClC-1 mutations begins to elucidate the role of the D10 segment in channel gating. Journal of Biological Chemistry 275:2999-3005

Plaster N, Uyama E, McKenna C, Ptácek LJ (1999) Genetic mapping of a locus for familial adult- onset myoclonic epilepsy (FAME). Neurology 53:1180-1183

Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptácek LJ (1999) Familial advanced sleep-phase syndrome: a short period circadian rhythm variant in humans. Nature Medicine 5:1062-1065

Bendahhou, S, Cummins, TR, Tawil, R, Waxman, SG, Ptácek LJ (1999) Activation and Inactivation of the Voltage-Gated Sodium Channel: Role of Segment S5 Revealed by a Novel Hyperkalaemic Periodic Paralysis Mutation. Journal of Neuroscience Jun 15;19(12):4762-71

Gouw LG, Castañeda MA, Jeri RF, Pulst SM, McKenna CK, Digre KB, Lee MS, Gomez C, Fischbeck K, Gardner M, Bird T, Ptácek LJ (1998) Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission. Human Molecular Genetics, 7:525-532