We are interested in understanding the mechanisms of various diseases involving the nervous system. In particular, there are two classes of neurological diseases that we are focusing on: demyelinating degenerative diseases and circadian rhythm disorders. My group has been using human genetic tools to identify genes involved in these disorders. Studying the disease mechanisms following the discovery of the genes will lead to unraveling of the pathogenesis of these disorders.
Multiple sclerosis is a common, often severe neurologic disorder for which the cause, cure and prevention are unknown and for which no specific diagnostic test exists. We are currently working on two projects that relate to demyelinating degenerative diseases of the nervous system. 1) Autosomal dominant leukodystrophy (ADLD) is clinically similar to the chronic progressive form of MS. Misdiagnosis of ADLD patients as having MS is common although ADLD and MS are readily distinguishable at autopsy. Many clinical features of this leukodystrophy are similar to those of MS including nystagmus, dysarthria, sensory loss, weakness, spasticity, hyperreflexia, and dysmetria. Further, cognitive and visual pathway abnormalities similar to those of MS are present in some of the ADLD patients. Bowel, bladder, and sexual dysfunction are common and are of roughly equal severity in both disorders. However, ADLD patients often have syncope and prolonged lethargic states due to postural hypotension caused by early and significant autonomic nervous system involvement. We have recently identified a tandem genomic duplication that causes ADLD. The duplication results in an extra copy of the gene encoding the nuclear lamina protein lamin B1 (LMNB1), and result in increased gene dosage of LMNB1 in brain tissue from affected individuals. 2) Multiple Sclerosis Associated with a Chromosomal Translocation. This phenotype is co-segregating with a balanced chromosome translocation. We also have identified the responsible mutation for this disorder, and functional characterization for this mutation is underway. We are using Drosophila , zebrafish, and mouse models to help us understand myelin biology. Our long term goal is to understand molecular mechanism of dysmyelination in these diseases (and of myelin synthesis, degeneration, and regeneration in general). Evidence has indicated that MS is a complex trait caused by interactions of genetic and environmental factors. An intensive effort has been made to identify the major genes influencing MS susceptibility but has yielded limited results. We are approaching this problem by studying rare monogenic disorders with an MS or MS-like phenotype to lead us toward a better understanding of the mechanism of myelin biology and the pathogenic process of common forms of MS.
Human Circadian Rhythm Genetics:
Another area of our research interest is in the study of circadian rhythm and sleep homeostasis. Circadian rhythm is one of the best models for studying human behavior. When we say "Genetics is everything", it may not be so far-fetched in truth if we come to recognize how much our behaviors are impacted by our genetic composition. Many of our physiological processes including heart beat, blood pressure, body temperature, and endocrine functions are subject to circadian regulation. However, the regulation of the overall behavior of an organism is the most overt and intriguing manifestation of circadian rhythmicity. The pursuit of the genetic and molecular basis of behavior is extremely complex because of the wide variation in "normal" individuals. Furthermore, behaviors such as sleep are confounded by social and familio-cultural influences that frequently lead us to override our biological clock and stay up later or wake up earlier than we otherwise would. Various agents including caffeine and alcohol also confound one's ability to understand the inherent rhythms dictating humans' activities. We have identified several mutations that are involved in regulation of human rhythmicity and sleep. Molecular studies in in vitro systems as well as in model organisms with human mutations are intensely pursued. Our long-term goal for this particular project is that as we find more mutations affecting human sleep patterns, we will be characterizing these mutations to assist us in understanding the human circadian clock and sleep.
Fu Y-H, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST, Oostra BA, Nelson DL, Caskey CT. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox . Cell 1991 Dec 20, 67 (6):1047-1056.
Fu Y-H, Pizzuti A, Fenwick,Jr., RG, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, DeJong P, Wieringa B, Korneluk R, Perryman BM, Epstein HF, Caskey CT. An unstable triplet repeat in a gene related to myotonic muscular dystrophy . Science 1992, 255:1256-1258.
Caskey CT, Pizzuti A, Fu Y-H, Fenwick RG Jr, Nelson DL. Triplet repeat mutations in human disease . Science 1992 May 8, 256 (5058):784-789.
Fu Y-H, Friedman DL, Richards S, Pearlman JA, Gibbs RA, Pizzuti A, Ashizawa T, Perryman MB, Fenwick RG Jr, Caskey CT. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy . Science 1993 Apr 9, 260 (5105):235-238.
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wejsman EM, Bird TD, Schellenberg GD, Tanzi RE. Candidate gene for the chromosome 1 familial Alzheimer's disease locus . Science 1995, 269:973-977.
Fu Y-H, Yu CE, Oshima J, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD (The first three authors contributed equally). Positional cloning of the Werner's syndrome gene . Science 1996 Apr 12, 272 (5259):258-261.
Coffeen CM, McKenna CE, Koeppen AH, Plaster NM, Maragakis N, Mihalopoulos J, Schwankhaus JD, Flanigan KM, Gregg RG, Ptácek LJ, Fu Y-H. Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31 . Hum Mol Genet. 2000 Mar 22, 9(5):787-793.
Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu Y-H. An h Per2 phosphorylation site mutation in familial advanced sleep-phase syndrome . Science 2001 Feb 9, 291 (5506):1040-1043.
Einum DD, Townsend JJ, Ptácek LJ, Fu, Y-H. Ataxin-7 expression analysis in controls and spinocerebellar ataxia type 7 patients . Neurogenetics 2001 Mar, 3(2):83-90.
Matilla A, Gorbea C, Einum DD, Townsend J, Michalik A, van Broeckhoven C, Jensen CC, Murphy KJ, Ptácek LJ, Fu Y-H. Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex . Hum Mol Genet. 2001 Nov 15, 10(24):2821-2831.
Einum D, Clark AM, Townsend JJ, Ptácek LJ, Fu Y-H. A novel central nervous system-enriched spinocerebellar ataxia type 7 gene product . Arch Neurol. 2003, 60:97-103.
Ptácek LJ, Fu YH. Channels and Disease: Past, Present, and Future . Arch Neurol. 2004 Nov; 61(11):1665-8.
Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu YH. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome . Nature. 2005 Mar 31;434(7033):640-4.
Padiath QS, Saigoh K, Schiffman R, Asahara H, Koeppen A, Hogan K, Ptácek LJ, Fu Y-H . Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet . 2006 Oct ; 38(10)1114-23. Epub 2006 Sep 3.
Xu Y, Toh KL, Jones CR, Shin JY, Fu Y-H, Ptácek LJ. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell. 2007 Jan 12:128(1):59-70.