Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2

Abstract

Episodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in CACNA1A, the gene encoding the pore-forming α1 subunit of P/Q-type voltage-gated Ca2+ channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients. CACNA1A is heavily spliced and some of the identified EA2 mutations are predicted to disrupt selective isoforms of this gene. Modulating splicing of CACNA1A may therefore represent a promising new strategy to develop improved EA2 therapies. Because RNA splicing is dysregulated in many other genetic diseases, several tools, such as antisense oligonucleotides, trans-splicing, and CRISPR-based strategies, have been developed for medical purposes. Here, we review splicing-based strategies used for genetic disorders, including those for Duchenne muscular dystrophy, spinal muscular dystrophy, and frontotemporal dementia with Parkinsonism linked to chromosome 17, and discuss their potential applicability to EA2.

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

“…These issues limit the definition of a clear-cut genotype-phenotype correlation for the clinician. On the bench side, a deeper understanding of implications of CACNA1A dysfunction on cerebrocerebellar circuitries and local plasticity phenomena at the cellular membrane may help to conceive common therapeutic strategies targeting symptoms across different phenotypes ( 37 ).…”

“…Several disease-associated missense variants lead to substitution of positively charged arginine in the segment S4 ( 29 , 34 – 36 ). An updated graphical overview of the known mutations in CACNA1A can be found in ( 37 ) and ( 38 ). Irrespective of the mutation type, CACNA1A diseases shown an autosomal dominant pattern of inheritance.…”

Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes

“…As well as being of importance for understanding normal developmental processes, AS is also of clinical relevance, since aberrant transcriptional processes are implicated in many diseases (Scotti & Swanson 2016). Disease-associated mutations can directly affect AS by disrupting existing splice sites and/or forming novel or cryptic sites, as observed in the VGCC CACNA1A gene in Episodic Ataxia Type 2 (Jaudon et al 2020). Alternatively, AS can alter disease presentation, as is seen in the case of Timothy Syndrome where the localisation of the disease-causing mutation in one of two mutually exclusive exons of CACNA1C determines syndrome severity (Splawski et al 2004).…”

“…The copyright holder for this preprint this version posted April 28, 2021. ; https://doi.org/10.1101/2021.04.27.441628 doi: bioRxiv preprint forming novel or cryptic sites, as observed in the VGCC CACNA1A gene in Episodic Ataxia Type 2 (Jaudon et al 2020). Alternatively, AS can alter disease presentation, as is seen in the case of Timothy Syndrome where the localisation of the disease-causing mutation in one of two mutually exclusive exons of CACNA1C determines syndrome severity (Splawski et al 2004).…”

CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

“…In the same F1394 position, a single nucleotide deletion (c.4182delC) that resulted in a putative truncated protein due to premature termination, was found in several members of an EA2 family showing variation of clinical symptoms among the carriers, ranging from severe early-onset (at the age of 1-2) weekly episodes to less severe phenotype with first attacks occurring in childhood and prolonged attack-free periods [ 22 , 23 ]. As all Ca V 2.1 truncations, it is expected to produce channel loss-of-function that is the cause of the majority of EA2 cases [ 1 ].…”