Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17

Abstract

Trinucleotide repeat expansions are dynamic mutations causing many neurological disorders, and their instability is influenced by multiple factors. Repeat configuration seems particularly important, and pure repeats are thought to be more unstable than interrupted repeats. But direct evidence is still lacking. Here, we presented strong support for this hypothesis from our studies on spinocerebellar ataxia type 17 (SCA17). SCA17 is a typical polyglutamine disease caused by CAG repeat expansion in TBP (TATA binding protein), and is unique in that the pure expanded polyglutamine tract is coded by either a simple configuration with long stretches of pure CAGs or a complex configuration containing CAA interruptions. By small pool PCR (SP-PCR) analysis of blood DNA from SCA17 patients of distinct racial backgrounds, we quantitatively assessed the instability of these two types of expanded alleles coding similar length of polyglutamine expansion. Mutation frequency in patients harboring pure CAG repeats is 2-3 folds of those with CAA interruptions. Interestingly, the pure CAG repeats showed both expansion and deletion while the interrupted repeats exhibited mostly deletion at a significantly lower frequency. These data strongly suggest that repeat configuration is a critical determinant for instability, and CAA interruptions might serve as a limiting element for further expansion of CAG repeats in SCA17 locus, suggesting a molecular basis for lack of anticipation in SCA17 families with interrupted CAG expansion.

Spinocerebellar ataxia type 17 associated with an expansion of 42 glutamine residues in TATA-box binding protein gene

“…This corresponds to the interrupted consensus repeat structure found in familial SCA17 cases. It is stable during transmission 13 14. Analysis using STRP markers D6S264, D6S281, D6S446 and D6S1590 linked to TBP indicated that the mutations arose independently in 2/II-1 and patient 4 of table 1 (data not shown).…”

“…The repeat expansions could not be determined in all affected family members. However, the well-documented stability of the observed repeat structure13 14 indicates that the patients carried identical repeat expansions.…”

Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals

“…Pure CAG repeats are less stable than repeats encoded by a mix of interspersed CAG and CAA triplets (Gao et al , 2008 ). An example of the latter is FoxP2, a transcription factor needed for speech and language development in humans, with a long, quite stable polyQ stretch of 40 glutamines (Bruce and Margolis , 2002 ;Enard et al , 2002 ;Webb and Zhang , 2005 ).…”

“…PolyQ tracts encoded by CAG repeats are particularly problematic due to their genetic instability caused by out-ofregister recombination or DNA strand slippage during replication (Gao et al , 2008 ), an effect that was also observed with other types of short repeats (e.g., Bois et al , 2001 ). Nine human neurodegenerative disorders, all of them inherited gain-of-function diseases, are caused by the expansion of CAG repeats.…”

Mutation Analysis of the TATA box-binding protein (TBP) gene in Chinese Han patients with spinocerebellar ataxia

“…Compared to the other SCA subtypes caused by expanded trinucleotide repeats, anticipation in SCA17 kindreds is rare because the interruption of CAA within the CAG repeat configuration of the TBP gene is considered significant in stabilizing the microsatellite. 9 The most common CAG repeat configuration in SCA17 patients is: (CAG)3(CAA)3(CAG)n 1 CAACAGCAA(CAG)n 2 CAACAG. Alleles without the characteristic CAA-CAG-CAA interruption will change the expanded allele size during intergenerational transmission.…”