Inheritance patterns of ATCCT repeat interruptions in spinocerebellar ataxia type 10 (SCA10) expansions

Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant cerebellar ataxia disorder, is caused by a non-coding ATTCT microsatellite repeat expansion in the ataxin 10 gene. In a subset of SCA10 families, the 5’-end of the repeat expansion contains a complex sequence of penta- and heptanucleotide interruption motifs which is followed by a pure tract of tandem ATCCT repeats of unknown length at its 3’-end. Intriguingly, expansions that carry these interruption motifs correlate with an epileptic seizure phenotype and are unstable despite the theory that interruptions are expected to stabilize expanded repeats. To examine the apparent contradiction of unstable, interruption-positive SCA10 expansion alleles and to determine whether the instability originates outside of the interrupted region, we sequenced approximately 1 kb of the 5’-end of SCA10 expansions using the ATCCT-PCR product in individuals across multiple generations from four SCA10 families. We found that the greatest instability within this region occurred in paternal transmissions of the allele in stretches of pure ATTCT motifs while the intervening interrupted sequences were stable. Overall, the ATCCT interruption changes by only one to three repeat units and therefore cannot account for the instability across the length of the disease allele. We conclude that the AT-rich interruptions locally stabilize the SCA10 expansion at the 5’-end but do not completely abolish instability across the entire span of the expansion. In addition, analysis of the interruption alleles across these families support a parsimonious single origin of the mutation with a shared distant ancestor.

10型脊髓小脑共济失调（Spinocerebellar ataxia type 10, SCA10）是一种常染色体显性遗传性小脑共济失调疾病，由共济失调蛋白10基因（ataxin 10 gene）内的非编码区ATTCT微卫星重复扩增所致。在部分SCA10家系中，重复扩增区域的5'端含有复杂的五核苷酸与七核苷酸插入基序，其3'端则接有一段长度未知的纯串联ATCCT重复序列。值得注意的是，携带此类插入基序的扩增序列与癫痫发作表型相关，且即便理论上插入序列本应使扩增重复序列趋于稳定，此类扩增仍表现出不稳定性。为探究携带插入序列的SCA10扩增等位基因仍不稳定这一表观矛盾，并明确不稳定性是否起源于插入区域之外，本研究针对来自4个SCA10家系的多代个体，利用ATCCT-PCR产物对SCA10扩增区域的5'端约1kb片段进行了测序。结果发现，该区域内的最大不稳定性出现在纯ATTCT重复序列区段的等位基因父系传递过程中，而中间的插入序列则保持稳定。总体而言，ATCCT插入序列仅发生1至3个重复单元的变化，因此无法解释疾病等位基因全长的不稳定性。我们由此得出结论：富含AT的插入序列可在5'端局部稳定SCA10扩增区域，但无法完全消除扩增区域全长的不稳定性。此外，对这些家系中的插入等位基因的分析支持该突变具有单一且简约的起源，即存在共同的远祖。