Our Research    This page contains tooltip text

The main research focus of the Hagerman laboratory is on the pathogenic mechanisms that cause fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). Although both fragile X syndrome and FXTAS are caused by CGG-repeat expansions in the fragile X mental retardation 1 (FMR1) gene; the two disorders affect different groups of individuals, and operate through entirely different molecular genetic mechanisms. Understanding the alterations of FMR1 gene expression that lead to these two separate disorders, and the development of targeted therapies for both fragile X syndrome and FXTAS, are the fundamental objectives of the lab.

Absence of FMRP

Schematic of the two separate pathogenic mechanisms leading to FXTAS (“RNA toxicity”) and fragile X syndrome (absence of FMR1 protein), depending on the size of the CGG repeat (Gold). For CGG repeats greater than 200 (full mutation range), the promoter region of the gene is hypermethylated (Pink) and silenced.

 

targeted therapies - Targeted therapies are those in which a specific feature of the gene, its RNA or protein product, or some feature of its pathogenic mechanism are specifically targeted (blocked or induced) to correct or circumvent the disease process. Examples would include reduction in FMR1 mRNA to treat FXTAS, or inducing the production of more FMRP to improve cognition and behavior for fragile X syndrome.

"RNA toxicity" refers to the direct induction/triggering by RNA of a disease process; in the case of FXTAS, this induction is likely the result of one or more proteins interacting with the CGG repeat to produce cellular dysfunction. The term "gain-of-function" refers to some new function of an RNA or protein that is not part of its normal function - for the FMR1 mRNA, this new function is the triggering of the pathogenic process leading to FXTAS, whereas its normal function is to be translated into FMRP