By: Clara O’Hara
SPTAN1
SPTAN 1 is a spectrin (a family of proteins playing a crucial part in the cell membrane) that provides instructions for making a cytoskeletal protein called alpha-II spectrin, which surfaces on the plasma membrane of eukaryotic cells. It is abundant in the brain and plays a crucial role in the formation and maintenance of cytoskeletons (network of protein filaments, thread-like structures, and tubules, tube-like structures, that extend throughout the cytoplasm of eukaryotic cells) in neurons.
Etiology of Epilepsy in SPTAN 1
Mutations in the cytoskeletal protein, the SPTAN-1 gene, have been viewed in starting epileptic encephalopathy and structural abnormalities contributing to the onset of epilepsy. For epileptic encephalopathy to occur among infants and younger children, a heterozygous mutation occurs in the SPTAN-1 gene.
There have been many cases leading to the identification of a non-heritable heterozygous mutation in the SPTAN-1 gene. Studying the expression of the non-heritable heterozygous mutation, harmful gene products interfere with the parts (spectrins) causing normal structural stability in non-covalent interactions of the cell membranes, particularly in red blood cells. This leads to decreased stability in the cell membrane, making it lose shape, integrity, and causing it to be susceptible to stress. The non-heritable heterozygous mutation in the SPTAN-1 gene also can disrupt the spaces between segments in the axon, causing functional changes to the neuronal charge in the brain. Along with this disruption, it may also be followed by only one copy of the SPTAN-1 gene, instead of two copies, and accumulations of spectrins. This causes epileptic encephalopathy through hyperexcitability of the neuronal charge and other effects.
Symptoms
EIEE is characterized by many severe developmental delays, motor coordination, and neurological abnormalities. Such symptoms include:
- Hypsarrhythmia
- Lack of Visual Attention
- Poor Head Control
- Feeding Difficulties
- Microcephaly
- Spastic quadriplegia
- Brain Imaging: Cerebral atrophy and hypomyelination
Diagnosis
It is most often difficult to diagnose mutation in the SPTAN-1 gene. There are some ways, however, that have helped identify mutation in the SPTAN-1 gene:
MRIs have been effective in finding a mutation in the SPTAN-1 gene through the identification of brain atrophy, detailed to be a symptom of the mutation. There is a reduced volume of white matter, atrophy/hypoplasia of the brainstem and cerebellum, and among other abnormalities.
Protein contact maps have also been effective in finding mutations in the SPTAN-1 gene through amino acid residues. Double immunostaining found that certain protein combinations, specifically α-II/β-II and α-II/β-III spectrins, were involved in clumping together (aggregation). A mutation called p.Q2202 del didn’t change the pattern in N2A cells, but in brain cells, it still caused aggregation, though in fewer cells. The findings suggest that the severity of symptoms might be linked to how much these proteins clump together. Interestingly, two patients with a certain gene duplication didn’t live long, while another patient with a different mutation survived longer despite severe movement problems.
Treatment
Although there are little to no studies looking at therapy specifically for SPTAN-1 gene, there have been recent developments in targeting pathogenic variants in spectrin including the SPTAN-1 gene, potentially leading to therapeutic intervention. Spatiotemporal mapping of spectrins has been helpful in evaluating the progression of spectrin, therefore providing when to treat for pathogenic variants of spectrin such as SPTAN-1 gene. In addition, the reintroduction of spectrin through animal models has allowed researchers to evaluate the pathological mechanisms involved in pathogenic variants, allowing researchers to know where and the cause of the pathogenic variants. When coupled with genomics and other impartial high-throughput molecular approaches, this comprehensive toolkit will pave the way for pinpointing targets through conventional therapeutic exploration—an area currently lacking in the study of spectrinopathies. Consequently, these tools will facilitate the adoption of promising technologies that could provide alternative, viable routes for treatment, including gene replacement and editing, as well as strategies based on antisense oligonucleotides182 (short sequences of nucleotides designed to specifically bind to complementary RNA sequences).
References
Account – Genecards Suite, www.genecards.org/cgi-bin/carddisp.pl?gene=SPTAN1. Accessed 3 Feb. 2024.
AL;, Lorenzo DN;Edwards RJ;Slavutsky. “Spectrins: Molecular Organizers and Targets of Neurological Disorders.” Nature Reviews. Neuroscience, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/36697767/. Accessed 3 Feb. 2024.
“Early Infantile Epileptic Encephalopathy – about the Disease.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/9255/early-infantile-epileptic-encephalopathy. Accessed 3 Feb. 2024.
Tohyama J;Nakashima M;Nabatame S;Gaik-Siew C;Miyata R;Rener-Primec Z;Kato M;Matsumoto N;Saitsu H; “SPTAN1 Encephalopathy: Distinct Phenotypes and Genotypes.” Journal of Human Genetics, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/25631096/. Accessed 3 Feb. 2024.
