Ying-Hui Fu, Ph.D.
	Molecular Studies of Human Circadian Rhythm and Demyelinating disorders
	Email: yhf@neugenes.org Websites: Fu Lab
Selected Publications | Complete Publications

I am interested in understanding the mechanisms of various diseases involving the nervous system. In particular, there are two classes of neurological diseases that I am 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: 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. Further, the strong Mendelian pattern of transmission of this disorder should be helpful in distinguishing it from chronic progressive MS. While familial clustering of MS exists, no large autosomal dominant families have been recognized. We have already identified the responsible mutation for this disorder and are characterizing the functional role of the mutation. 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. Functional characterization for this mutation is underway. We are using Drosophila, zebrafish, and mouse models to help us understand myelin biology. My 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. Whole-genome screen in MS families has proven to be more difficult and complicated than predicted. I am approaching this problem by studying rare monogenic disorders with an MS or MS-like phenotype to lead me toward pathogenic mechanisms of more common mechanisms of myelin biology and disease forms of MS.

Human Circadian Rhythm Genetics: Another area of my research interest is in the study of circadian rhythm. 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 to 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. Molecular studies in in vitro system as well as in model organisms with human mutations are intensely pursued. My long-term goal for this particular project is that as we find more mutations that are affecting human sleep pattern, we will characterizing these mutations to assist us understand human circadian clock and sleep.

Selected Publications

Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu Y-H. Functional consequences of a CKI mutation causing familial advanced sleep phase syndrome. Nature. 2005;434:640-4.

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.

Information last updated April 2007