Neuroscience Graduate Program at UCSF
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.
William Hallows, Postdoctoral Fellow
Shen-Yi Bruce Howng, Postdoctoral Fellow
Yong Huang, Postdoctoral Fellow
Shu-Ting Ling, Postdoctoral Fellow
Luoying Zhang, Postdoctoral Fellow
Ying Zhang, Laboratory Assistant
Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptáček LJ. Familial advanced sleep-phase syndrome: a short period circadian rhythm variant in humans. Nat Med. 1999;5:1062-1065.
Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptáček LJ, Fu Y-H. An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep-Phase Syndrome. Science. 2001;291:1040-1043.
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, Ptáček LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s Syndrome. Cell. 2001, 105:511-519.
Skradski S, Clark A, Jiang H, White S, Fu Y‑H, Ptáček LJ. A novel gene causing a Mendelian audiogenic mouse epilepsy. Neuron. 2001, 31:537-544.
Matilla A, Gorbea C, Einum DD, Townsend J, Michalik A, van Broeckhoven C, Jensen CC, Murphy KJ, Ptáček LJ, Fu YH. Association of ataxin-7 with the proteasome subunit S4 of the 10S regulatory complex. Hum Mol Genet. 2001, 10:2821-2831.
Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu H-Y, Ptáček LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003 Jun 10;60(11):1811-6.
Bendahou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu Y-H, Ptáček LJ. Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem. Dec. 19, 2003 ;278(51):51779-85.
Lee H-Y, Xu Y, Huang Y, Ahn A, Bruno M, Abramowicz M, Pandolfo M, Auburger G, Averyanov Y, Kwieciński H, Servidei S, Grimes D, Lang T, Nielsen J, Fu Y-H, Ptáček LJ. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet. 2004, Vol. 13(24);3161-3170.
Xu Y, Padiath Q, Shapiro R, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptáček LJ, Fu Y-H. Functional consequences of a CK1δ mutation causing familial advanced sleep phase syndrome. Nature. 2005: Vol. 434:640-644.
Padiath QS, Saigoh K, Schiffmann R, Asahara H, Koeppen A, Hogan K, Ptáček LJ, Fu YH. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet. 2006 Oct; 38(10):1114-23.
Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptáček LJ. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell. 2007 Jan 12; 128(1):59-70.
Shin D, Shin JY, McManus M, Ptáček LJ, Fu YH. Dicer ablation in oligodendrocytes provokes neuronal impairment in mice. Annals of Neurology. 2009 Dec; 66(6):843-57.
Ryan D, Dias da Silva M, Soong TW, Fontaine B, Donaldson M, Kung AWC, Jongjaroenprasert W, Liang MC, Khoo D, Cheah JS, Ho SC, Bernstein H, Maciel R, Brown R, Ptáček LJ. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010 Jan 8; 140(1):88-98.
Lee HY, Huang Y, Bruneau N, Roll P, Roberson E, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee W-L, Lynch DR, Mohammed S, Müller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong B-W, Swoboda KJ, Tucker S, Wood N, Hanna M , Bowcock AM, Szepetowski P, Fu Y-H, Ptáček LJ. Mutations in the novel protein PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Reports. 2012 Jan 26; 1(1):2-12.
Lee HY, Nakayama J, Xu Y, Fan X, Karouani M, Shen Y, Pothos E, Hess E, Fu Y-H, Edwards RH, Ptáček LJ. Dopamine dysregulation in a mouse model of paroxysmal non-kinesigenic dyskinesia. J Clin Invest., 2012 Feb 1;122(2):507-18.
Kategaya LS, Hilliard A, Zhang L, Asara JM, Ptáček LJ, Fu Y-H. CK1δ and CK1ε Proteomics Reveal Prohibitin 2 as a Novel Regulator of Circadian Rhythms. PLoS One. 2012;7(2):e31987.
Russell JF, Steckley JL, Coppola G, Hahn AF, Kornberg Z, Huang A, Merriman B, Klein E, Choi M, Lee H-Y, Kirk A, Nelson-Williams C, Gibson G, Lifton RP, Geschwind DH, Fu Y-H, Ptáček LJ. Familial Cortical Myoclonus Caused by Mutation in NOL3. Annals of Neurology. 2012 Aug;72(2):175-83.
Zhang L, Abraham D, Nishino S, Oster H, Fujiki N, Gregor Eichele, Fu YH, Ptáček LJ. PKCγ Participates in the Entrainment of the Cerebral Circadian Clocks by Feeding. Proc Natl Acad Sci USA. 2012 Dec 11;109(50):20679-84.
Kaasik K, Allen JJ, Kivimae S, Chalkley R, Huang Y, Kissel H, Burlingame AL, Shokat KM, Ptáček LJ, Fu YH. Reciprocal regulation of Circadian Clock through GSK3β and O-linked N-acetylglucosaminylation. Cell Metabolism. 2013;17:291–302.
Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, Wang X, Gao X, Huang M, Yan J, Yang L, Liu Y, Ptáček LJ, Xu Y. Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock. Proc Natl Acad Sci USA. 2013 Mar 19;110(12):4750-5.
Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, Lee H-Y, Jones CR, Fu Y-H, Charles AC, Ptáček LJ. Casein kinase Iδ mutations in familial migraine and advanced sleep phase. Science Translational Medicine. 2013 May 1;5(183):183ra56.Heng MY, Lin S-T, Verret L, Huang Y, Kamiya S, Palop JJ, Huang EJ, Ptáček LJ, Fu Y-H. Lamin B1, a Novel Myelin Regulator, Mediates Cell-Autonomous Neuropathology in a Murine ADLD Model. J Clin Invest., 2013;123:2719-2729.
Louis Ptacek, M.D.
UCSF Mission Bay, Box 2922
Fu and Ptacek Laboratories
1550 4th Street, room 548F
San Francisco, CA 94143