Research Grant Award

Tohru Matsuura, MD

Baylor College of Medicine, Molecular and Human Genetics The Role of Interruptions in SCA 10 expansion and disease

Spinocerebellar ataxia type 10 (SCA 10) is an autosomal dominant neurodegenerative disorder clinically characterized by a unique combination of progressive ataxia and seizures. The cause of SCA 10 is an unstable expansion of an ATTCT pentanucleotide repeat in intron 9 of the SCA 10 gene mapped to the long arm of chromosome 22.

The ATTCT repeat is a unique motif located in an intron and the size of expansion in SCA 10 is one of the largest among diseases caused by repeat expansion. The gender of the transmitting parent, the motif of the repeat unit, the length of the repeat, the location of the repeat in the gene, and the surrounding sequences (i.e., cis elements) may influence the unique characteristics of ATTCT repeat instability shown in our previous studies. Among them, we believe the sequence variation of the repeat itself is the key to the instability. Investigation of the instability mechanism must provide insight into the disease mechanism, potentially leading to therapeutic interventions.

Although it is very difficult to characterize large repetitive tracts, our newly developed techniques have enabled us to clone the ATTCT expansion. We will be able to analyze the sequence configurations of the SCA 10 expansion in all identified SCA 10 families. After cloning the expansion, we are also planning to analyze the effect of sequence interruptions on nucleosome assembly on the SCA 10 ATTCT tracts, because chromatin packaging and nucleosome assembly can regulate many aspects of DNA metabolism.

We now seek funding from the NAF for further characterization of the SCA 10 expansion, to continue this work in the hope of obtaining sufficient data to compete for funding from other sources.