Haplotype Analysis of SCA8 Expansion Chromosomes

To better understand the origin of the SCA8 expansion and the reduced penetrance of the disease, haplotype analysis was performed on a panel of 37 SCA8 families from the USA, Canada, Japan, and Mexico, 13 SCA8 expansionpositive samples sent to Athena Diagnostics for ataxia testing, seven control samples with expansions, and 14 expansion carriers with psychiatric diseases (Ikeda et al. 2004). A total of 17 polymorphic short tandem repeat markers were analyzed, including 13 newly developed markers that span an approximately 1 Mb region flanking the SCA8 d(CTG) repeat.

Two ancestrally related haplotypes (A and A') were observed in the Caucasian population, which included SCA8 and psychiatric patients, and controls—indicating a common origin for the pathogenic and nonpathogenic i i (ctg)n i ci (mn-a) haplotype r i ii ii (ctg)n in^^i c26b haplotype R

i iii (ctg)n ^h c30 haplotype r i i (ctg)n L i i c31 haplotype r r i i [cto)ny v vi c13b haplotype r

Fig. 5 Proposed summary of the ancestral origins of the SCA8 expansion haplotypes based on the analysis of 37 SCA8 families. The current haplotypes are likely to have arisen from a small number of ancestral recombination and microsatellite instability events as illustrated. R indicates a recombination event and the asterisk symbolizes an area with microsatellite repeat instability. (Reproduced with permission from University of Chicago Press and Ikeda et al. (2004) Am J Hum Genet 75:3-16. © 2004 by The American Society of Human Genetics. All rights reserved)

expansions within the Caucasian population (Ikeda et al. 2004) (Fig. 5). Two other distinct haplotypes were identified for the Japanese and Mexican ataxia families (B and C, respectively) (Fig. 5). These results indicate that independently arising SCA8 expansions are found in ataxia families with various ethnic backgrounds, further supporting the direct role of the d(CTG) expansion in disease pathogenesis.

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