Paul J. Hagerman, M.D., Ph.D.

Professor

Room 4455, Tupper Hall
Ph: (530) 754-7266
Fax: (530) 754-7269
pjhagerman@ucdavis.edu

The principal objective of the Hagerman laboratory is a greater understanding of the molecular basis of clinical involvement in fragile X syndrome and autism, with the goal of developing effective therapies for those neurodevelopmental disorders. We are also investigating a newly discovered neurodegenerative disorder, FXTAS, associated with the fragile X gene. Our efforts combine clinical and basic molecular research, the latter involving studies of gene expression at the level of transcription and translation.

Fragile X syndrome is the leading inherited form of mental impairment, affecting about one person in 3,000 worldwide. This disorder is caused by large expansions of a three-base (CGG) repeat within the fragile X gene. For expansions of more than about 200 repeats (full mutation range), the gene generally becomes silent. In the absence of the protein product, FMRP, brain development is impaired. The laboratory is pursuing the development of new approaches for treating fragile X syndrome. We believe that small molecules, including modified DNA and RNA species, that can be targeted to the fragile X gene or its message will prove to be effective agents for the treatment of fragile X.
Current areas of research address the following questions regarding expression of the fragile X gene:

• Why does the fragile X gene remain active in some individuals with fragile X syndrome, even though such individuals possess little or no FMRP?
• What are the signals that tell the gene to shut down, and can these "silencing" signals be blocked or reversed?
• Why does the fragile X gene produce as much as ten times more message than normal in some individuals, while protein levels remain below normal?
• What are the signals that tell the gene to produce higher-than-normal levels of message?
• What does the protein product of the fragile X gene (FMRP) do?
• Why is FMRP production reduced even though message levels are high?

We have recently identified a new neurological disorder in adult carriers of small CGG expansions (55 to 200 repeats; premutation range) who are over 50 years of age. This disorder, called Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), includes progressive action tremor, ataxia and cognitive decline, and has associated findings of neuropathy and emotional disturbances. We estimate that more than 25 percent of all carriers could be affected with this progressive disorder. FXTAS appears to be distinct from fragile X syndrome, although it is associated with the FMR1 gene.
Current areas of research on FXTAS are aimed at the following questions:

• What is the basis for the progressive clinical findings, since FMRP levels are generally within or close to the normal range?
• Could this syndrome be due to overexpression of the fragile X gene message, which is high in these individuals?
• Why don´t all carriers have this disorder? Are other genes involved as well?

Autism is an increasingly common behavioral disorder consisting of substantially reduced social interactions, impaired or absent language development, and patterned, repetitive behaviors. However, the causes of autism remain obscure. Our laboratory is part of an NIH-funded Center that is investigating the underlying causes, both genetic and environmental, of autism and autism spectrum disorders. The experimental approaches are varied, and will include expression profiling (microarray) analysis and various proteomics methodologies. Our short-term objective is the identification of "biomarkers" that could be used to predict which neonates will go on to develop autism (and which could be prevented from such progression). Our long-term goal is the development of specific therapeutic approaches for the treatment of autism.

There are several computational problems that will continue to receive attention in our laboratory. Such problems include the development of better tools for the global analysis of microarray and proteomics data.

1. Cohen S, Masyn K, Adams J, Hessl D, Rivera S, Tassone F, Brunberg J, DeCarli C, Zhang L, Cogswell J, Loesch D, Leehey M, Grigsby J, Hagerman PJ, Hagerman R.
   Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.
   Neurology. 2006 Oct 24;67(8):1426-31.
   
2. Dodds ED, An HJ, Hagerman PJ, Lebrilla CB.
   Enhanced peptide mass fingerprinting through high mass accuracy: Exclusion of non-peptide signals based on residual mass.
   J Proteome Res. 2006 May;5(5):1195-203.
   
3. Hagerman RJ, Ono MY, Hagerman PJ.
   Recent advances in fragile X: a model for autism and neurodegeneration.
   Curr Opin Psychiatry. 2005 Sep;18(5):490-6.
   
4. Greco CM, Berman RF, Martin RM, Tassone F, Schwartz PH, Chang A, Trapp BD, Iwahashi C, Brunberg J, Grigsby J, Hessl D, Becker EJ, Papazian J, Leehey MA, Hagerman RJ, Hagerman PJ.
   Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).
   Brain. 2006 Jan;129(Pt 1):243-55. Epub 2005 Dec 5.
   
5. Iwahashi CK, Yasui DH, An HJ, Greco CM, Tassone F, Nannen K, Babineau B, Lebrilla CB, Hagerman RJ, Hagerman PJ.
   Protein composition of the intranuclear inclusions of FXTAS.
   Brain. 2006 Jan;129(Pt 1):256-71. Epub 2005 Oct 24.
   
6. Arocena DG, Iwahashi CK, Won N, Beilina A, Ludwig AL, Tassone F, Schwartz PH, Hagerman PJ.
   Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells.
   Hum Mol Genet. 2005 Dec 1;14(23):3661-71. Epub 2005 Oct 20.
   
7. Hessl D, Tassone F, Loesch DZ, Berry-Kravis E, Leehey MA, Gane LW, Barbato I, Rice C, Gould E, Hall DA, Grigsby J, Wegelin JA, Harris S, Lewin F, Weinberg D, Hagerman PJ, Hagerman RJ.
   Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation.
   Am J Med Genet B Neuropsychiatr Genet. 2005 Nov 5;139(1):115-21.
   
8. Jacquemont S, Orrico A, Galli L, Sahota PK, Brunberg JA, Anichini C, Leehey M, Schaeffer S, Hagerman RJ, Hagerman PJ, Tassone F.
   Spastic paraparesis, cerebellar ataxia, and intention tremor: a severe variant of FXTAS?
   J Med Genet. 2005 Feb;42(2):e14. No abstract available.
   
9. Garcia Arocena D, Louis ED, Tassone F, Gilliam TC, Ottman R, Jacquemont S, Hagerman PJ. Screen for expanded FMR1 alleles in patients with essential tremor.
   Mov Disord. 2004 Aug;19(8):930-3.
   
10. Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg JA, Tassone F, Hessl D, Harris SW, Zhang L, Jardini T, Gane LW, Ferranti J, Ruiz L, Leehey MA, Grigsby J, Hagerman PJ.
    Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.
    Am J Hum Genet. 2004 May;74(5):1051-6. Epub 2004 Apr 2.
    
11. Hagerman PJ, Hagerman RJ.
    The fragile-X premutation: a maturing perspective.
    Am J Hum Genet. 2004 May;74(5):805-16. Epub 2004 Mar 29. Review. Erratum in: Am J Hum Genet. 2004 Aug;75(2):352.
    
12. Jacquemont S, Farzin F, Hall D, Leehey M, Tassone F, Gane L, Zhang L, Grigsby J, Jardini T, Lewin F, Berry-Kravis E, Hagerman PJ, Hagerman RJ.
    Aging in individuals with the FMR1 mutation.
    Am J Ment Retard. 2004 Mar;109(2):154-64.
    
13. Hagerman PJ, Hagerman RJ.
    Fragile X-associated tremor/ataxia syndrome (FXTAS).
    Ment Retard Dev Disabil Res Rev. 2004;10(1):25-30. Review.
    
14. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, Zhang L, Jardini T, Gane LW, Harris SW, Herman K, Grigsby J, Greco CM, Berry-Kravis E, Tassone F, Hagerman PJ.
    Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population.
    JAMA. 2004 Jan 28;291(4):460-9.
    
15. Beilina A, Tassone F, Schwartz PH, Sahota P, Hagerman PJ.
    Redistribution of transcription start sites within the FMR1 promoter region with expansion of the downstream CGG-repeat element.
    Hum Mol Genet. 2004 Mar 1;13(5):543-9. Epub 2004 Jan 13.