CACNA1A. CACNA1A is a large gene with a long history. Its first gene-disease association was with spinocerebellar ataxia type 6 (SCA6), an adult-onset progressive neurological disorder. Next, it was found to be associated with episodic ataxia and familial hemiplegic migraine. It took several more years before it was also found to be associated with epilepsy, developmental delay, and a more severe form of hemiplegic migraine. Here is a blog post on the range of neurological disorders associated with CACNA1A and the mechanism driving it.
Figure 1. The CACNA1A gene codes for two proteins: α1A, a pore-forming subunit of the P/Q-type calcium channel, and α1ACT, a transcription factor involved in the growth and function of Purkinje cells. Translation for α1A begins with the start of the gene, while translation for α1ACT starts a cryptic internal ribosomal entry site (IRES). Spinocerebellar ataxia type 6 (SCA6) is caused by expansion of the polyQ region within the final exon of CACNA1A due to toxic buildup of abnormal α1ACT protein. Other CACNA1A-related disorders are caused by loss of gain of function within the P/Q-type calcium channel.
SCA6. While the phenotypic spectrum of CACNA1A is large, SCA6 stands out as unique among the range of disorders. For one, the onset is typically in the 40s-50s, with a wide range between 19-73 years of age. This is in stark contrast to the other phenotypes, which typically present in early childhood. In addition, SCA6 is a progressive disorder. Although there are reports of cerebellar atrophy or brain damage from hemiplegic migraines in the other CACNA1A-related disorders, these disorders have an overall stable course and are either developmental or episodic in nature. In fact, some neurological features may improve over time as children grow and develop. However, there is some overlap: SCA6 can initially present with episodic ataxia, and the developmental or epilepsy phenotypes of CACNA1A can also include progressive ataxia.
Mutation. While there is still a lot of work to do to understand the genotype-phenotype correlations in CACNA1A, one correlation is quite clear – while most disorders related to CACNA1A are caused by deletions or point mutations, SCA6 is caused by a repeat expansion. In the last exon of the gene, there is a stretch of CAG trinucleotide repeats. These trinucleotides, when translated into amino acids, become glutamine which is represented by the letter Q, hence this section is called a polyQ tract. If a person has 20 or more repeats in this section, they will develop a toxic buildup of abnormal protein, leading to damage in the cerebellum and, subsequently, the features of SCA6. 18 or fewer repeats is typical, with no features of spinocerebellar ataxia. Previous papers have shown families where individuals with the same variant (missense or CAG repeat expansion) can have either a familial hemiplegic migraine phenotype or an SCA6 phenotype, or where an individual with a missense variant had a classic SCA6 phenotype. However, this is rare.
Protein. Many of these differences can be explained by the fact that CACNA1A is bicistronic, meaning it codes for two different proteins. The disorders we study in our lab are caused by abnormalities within the pore-forming α1A subunit of the Cav2.1 channel, a P/Q-type voltage-gated calcium channel. A variant related to this protein can either cause a loss of function (loss of the protein or reduced functioning), gain of function (new abnormal properties emerge, such as reduced threshold for opening), or mixed effects (some properties of the channel demonstrating loss of function and others demonstrating gain of function). Meanwhile, SCA6 is associated primarily with α1ACT, a transcriptional factor. This protein promotes the growth, development, and function of Purkinje cells, which are neurons of the cerebellum.
Translation. The primary α1A transcript expressed in the brain (NM_001127221) starts from the beginning of the CACNA1A gene and includes the majority of exons in the gene, but does not include the last exon – exon 47. Translation for α1ACT starts at a cryptic internal ribosomal entry site (IRES) towards the end of the gene, including exon 47 with the CAG repeat tract. It is therefore a much shorter protein than α1A, as it skips much of the beginning and middle of the full CACNA1A gene. Blocking the IRES halts abnormal α1ACT production, and rescues an SCA6 phenotype in mice. Of note, this methodology is a major area of research for treatment in adults with SCA6, especially since reduction of α1ACT protein in adults is well-tolerated. Current research aims to use antisense oligonucleotides (ASOs) to block the entry site, and should in theory leave α1A production intact.
Why it matters. When looking up the CACNA1A gene, SCA6 inevitably comes up as an associated phenotype. However, automated lab reports or a rushing clinician may note a pathogenic CACNA1A variant in a patient, associate the gene with SCA6, and then declare the variant to be diagnostic of SCA6, all without consideration of the type of variant the patient has or their presenting phenotype. For the vast majority of patients with non-repeat expansion variants, this label of SCA6 can lead to confusion about diagnosis, prognosis and treatment. Given that SCA6 is adult-onset, the typical childhood onset of other CACNA1A-related disorders could lead families to think that their child’s variant must not be the answer. In addition, SCA6 is a slowly progressive disorder, while other disorders are generally stable and do not get worse over time. On the other hand, the seizures and hemiplegic migraines that can be seen in the other CACNA1A-related disorders can be clinical emergencies requiring urgent treatment, which is not the case in SCA6. Finally, the treatments are different as well. Often the treatments are symptomatic, and non-specific to the causative gene or genetic variant. However, there are several active clinical trials of various medications for adults with SCA6, but none for other CACNA1A-related disorders. SCA6 is also a clearer target for an ASO or other gene therapy, as knocking out expression of α1ACT appears to rescue an SCA6 phenotype in mice. Furthermore, these affected individuals are adults, with typical brain development before the onset of symptoms. Simply halting progression of the disorder would be a huge benefit to such patients. While we remain hopeful that gene therapies or other targeted therapies could help treat the seizures and hemiplegic migraines in CACNA1A, it is unlikely that any such treatment could treat the developmental delays that are present in so many of the affected children by the time they receive their CACNA1A diagnosis.
Summary. CACNA1A is a gene that codes for two separate proteins – one primarily involved in SCA6, an adult onset slow progressing ataxia disorder, and the other primarily involved in a variety of childhood-onset neurological conditions. The genetic mechanisms – repeat expansion versus point mutation or deletion – are distinct, as are many of the features. Genetic labs, neurologists, medical geneticists, genetic counselors, and others involved with the diagnosis of such conditions should take care to note the type of variant and clinical presentation present in a patient, and not apply a phenotypic label simply because of the gene involved. Furthermore, moving beyond broad phenotypic and genetic descriptions will allow for greater precision in individualized care and the development of targeted therapeutic strategies.