Ed Grabczyk

Dr. Ed Grabczyk is investigating the molecular basis of DNA repeat expansion disorders. Such genetic disorders arise when an unstable DNA repeat expands beyond a critical length. Expansion to a pathogenic size can occur between generations, making inheritance of these "dynamic mutations" appear to be complex. This locus-specific DNA instability often involves a trinucleotide repeat, so these are sometimes called triplet expansion diseases. Examples include the most common form of inherited mental retardation, fragile X syndrome, and the most common inherited ataxia, Friedreich ataxia (FRDA). The interactions between DNA structure, transcription and replication that elicit repeat expansion diseases are a central theme in the lab.

Repeat expansion disease etiology reflects both the sequence expanded and its location within the affected gene. For instance, in Huntington's disease and at least seven other dominant ataxias, CAG*CTG expansion in a coding region makes a toxic elongated polyglutamine tract. In fragile X, CGG*CCG expansion in the 5' end of the affected gene leads to hypermethylation of the promoter and transcriptional silencing. FRDA represents a new paradigm for repeat expansion disease etiology. GAA*TTC expansion in an intron of the FRDA gene reduces expression of frataxin, an essential mitochondrial protein. The severity of frataxin reduction corresponds to GAA*TTC tract length. The neurodegeneration and cardiomyopathy that ensues is relentlessly progressive, often lethal, and currently has no treatment or cure. The GAA*TTC repeat reduces gene expression by a novel mechanism that involves the formation of triple-stranded DNA during transcription.

A major focus is to understand in detail how GAA*TTC tracts reduce gene expression in human cells, and why this reduction is not as severe in patients of Acadian descent. FRDA is present at a higher than expected frequency in people of Acadian heritage, including the "Cajuns" of Louisiana. In Acadians, for a given expansion length, the age of onset is later, the disease course is milder and survival time is longer than that of the general FRDA population. DNA and cell lines derived from the Acadian people of Louisiana may provide a key to alleviating the disease in all FRDA patients.

Selected Publications:

Grabczyk E, Kumari D and Usdin K, Fragile X syndrome and Friedreich's ataxia: Two different paradigms for repeat induced transcript insufficiency., Brain Research Bulletin, 56, 367-373, 2001.

Grabczyk E and Usdin K, Alleviating transcript insufficiency caused by Friedreich's ataxia triplet repeats., Nucleic Acids Research 28, 4930-4937, 2000.

Grabczyk E and Usdin K, The GAA*TTC triplet repeat expanded in Friedreich's ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner., Nucleic Acids Research 28, 2815-2822, 2000.

Grabczyk E and Usdin K, Generation of microgram quantities of trinucleotide repeat tracts of defined length, interspersion pattern and orientation., Analytical Biochemistry 267, 241-243, 1999.

Grabczyk E and Fishman MC, A long purine*pyrimidine homopolymer acts as a transcriptional diode., J. Biol. Chem. 270, 1791-1797, 1995.

Contact info: egrabc@lsuhsc.edu