The genetic and molecular features of the intronic pentanucleotide repeat expansion in spinocerebellar ataxia type 10

Abstract

Spinocerebellar ataxia type 10 (SCA10) is characterized by progressive cerebellar neurodegeneration and, in many patients, epilepsy. This disease mainly occurs in individuals with Indigenous American or East Asian ancestry, with strong evidence supporting a founder effect. The mutation causing SCA10 is a large expansion in an ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene. The ATTCT repeat is highly unstable, expanding to 280–4,500 repeats in affected patients compared with the 9–32 repeats in normal individuals, one of the largest repeat expansions causing neurological disorders identified to date. However, the underlying molecular basis of how this huge repeat expansion evolves and contributes to the SCA10 phenotype remains largely unknown. Recent progress in next-generation DNA sequencing technologies has established that the SCA10 repeat sequence has a highly heterogeneous structure. Here we summarize what is known about the structure and origin of SCA10 repeats, discuss the potential contribution of variant repeats to the SCA10 disease phenotype, and explore how this information can be exploited for therapeutic benefit.

Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability

“…Two other SCAs types are also caused by pentanucleotide repeats: SCA10, associated with an ATTCT repeat expansion in ATXN10 , 40 and SCA31, associated with an AATGG expansions in BEAN1 41 . SCA10 expansions are mainly found in Latin American countries (with a probable founder effect originating from the Indigenous American population) and are associated with a clinically variable phenotype, either presenting as a pure cerebellar ataxia or as a combination of ataxia and seizures 42 . Interruptions, that is, the presence of alternative motifs such as ATTGT, ATCCT, or ATTCC within the expansions, have been associated with an increased risk of epilepsy 43 .…”

“…41 SCA10 expansions are mainly found in Latin American countries (with a probable founder effect originating from the Indigenous American population) and are associated with a clinically variable phenotype, either presenting as a pure cerebellar ataxia or as a combination of ataxia and seizures. 42 Interruptions, that is, the presence of alternative motifs such as ATTGT, ATCCT, or ATTCC within the expansions, have been associated with an increased risk of epilepsy. 43 Recent evidence even suggests that only interrupted expansions are pathogenic, whereas pure expansions composed of ATTCT repeats are either nonpathogenic or associated with late onset Parkinsonism, a finding reminiscent of pathological repeat configurations observed in FAME.…”

Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances

“…These foci sequester key RNA-binding proteins that perturb RNA-dependent RNA homeostasis, which may lead to cytotoxicity ( Figure 2 ) ( Zhang and Ashizawa, 2017 ). For example, RNA foci formed by the accumulation of AUUCU expansion in SCA10 can sequester heterogeneous cytosolic ribonucleoprotein K and impair its function, and its down-regulation can induce translocation and accumulation of protein kinase Cδ in the mitochondria, which subsequently triggers the caspase-3-mediated apoptotic pathway ( Kurosaki and Ashizawa, 2022 ). Repeated ATTTC expansion of the DAB1 gene leads to overexpression of DAB1 and induces an RNA switch, causing upregulation of the reelin-DAB1 and PI3K/AKT signaling pathways in the cerebellum of patients with SCA37, leading to cerebellar neuronal degeneration ( Corral-Juan et al, 2018 ).…”

Pentanucleotide repeat‐related disorders: Genetics and bioinformatic discovery and detection

“…14 This insertion, which was detected in all SCA31 individuals, occurred in a region containing TAAAA repeats. Two combined strategies have been carried out to find the novel ATTTC tandem repeat in the middle of a very Total pentanucleotide repeat size: 1, 13 2, 21 3, 49 4, 14 5, 1 6, 27 7, 26 8, 11 9, 12 10, 50 11, 2 12, 16 13, 51 14, 3 15, 4 16. 5 large polymorphic ATTTT tandem repeated sequence, in a 5′ untranslated region (UTR) intron of the DAB1, reelin adaptor protein gene, as the cause of SCA37.…”

“… a Total pentanucleotide repeat size: 1, 13 2, 21 3, 49 4, 14 5, 1 6, 27 7, 26 8, 11 9, 12 10, 50 11, 2 12, 16 13, 51 14, 3 15, 4 16 5 …”