Chapter 29 - Spinocerebellar Ataxia Type 10: A Disease Caused by an Expanded (ATTCT)n Pentanucleotide Repeat

Abstract

This chapter focuses on spinocerebellar ataxia type 10 (SCA10) that is an autosomal dominant disease caused by a large (4–22.5 kb) expansion of an (ATTCT)n pentanucleotide repeat in intron 9 of the ataxin-10 (ATXN10) gene on chromosome 22ql3.3. SCA10 is the only human disease caused by an expansion of a pentanucleotide repeat and has been found only in limited populations on the American continents. The principal clinical phenotype of SCA10 is cerebellar ataxia with or without epilepsy. Epilepsy frequently afflicts Mexican families, but peculiarly spares Brazilian families. Expanded (ATTCT)n repeats in some SCAIO patients examined were interrupted by various penta-, hexa-, and heptanucleotide repeat units. Expanded repeats show repeat-size mosaicism in somatic cells and sperm; however, the pattern of mosaicism is stable over time in the blood cells of adult patients in vivo. Paternal transmission of an expanded allele frequently results in an increase or a decrease in the repeat size in the offspring. The instability observed with paternal transmission may be attributable to the repeat-size mosaicism in sperm. In contrast, the repeat size is remarkably stable with maternal transmission, suggesting relative stability of the expanded repeat in oocytes. In vitro uninterrupted (ATTCT)n repeats form unpaired DNA structure. The pathogenic mechanism of SCA10 is unknown. However, because the (ATTCT)n repeat is located in an intron, the mutation is not translated into the protein sequence. Loss of ATXN10 function and RNA-mediated gain of function are currently under investigation as potential pathogenic models of SCA10.