Linker mutations in SCN2A and Ohtahara syndrome
Rajalaxmi Natarajan, PhD
Rajalaxmi Natarajan, PhD
November 14, 2014
Sodium channels are a type of ion channels present on the cell membrane that allow sodium ions to move freely into the cells. Sodium channel function is extremely crucial for excitable cells such as neurons and muscles since it is required for the generation of action potentials. Each neuronal cell type has various types of sodium channels based on their subunit composition. Mutations in many sodium channel subunits are known to result in one or multiple types of epilepsies.
In humans, voltage-gated sodium channels are comprised of 9 types of a subunits, each of which is encoded by a different SCN gene. Mutations in SCN1A gene result in a wide range of devastating epilepsies whereas majority of inherited mutations in SCN2A result in mild forms of epilepsy. Recently, however, few de novo SCN2A mutations have been found in patients with severe epilepsies like Dravet syndrome.
A study by Nakamura et al1, published in the September 2013 issue of Neurology further explores the association between SCN2A mutations and severe forms of early onset epileptic encephalopathies (EOEE). In this study, high-resolution DNA analysis and exome (protein coding part of the genome) sequencing of 328 EOEE patients identified 14 novel SCN2A mutations in patients with severe developmental delays and intractable epilepsies. Interestingly, majority of these mutations occurred spontaneously and were found in patients with severe EOEEs such as Ohtahara or West syndromes.
The most interesting correlative observation that emerges from this study is that SCN2A mutations that cause benign epileptic phenotypes typically reside in the transmembrane domains of SCN2A protein whereas all the 9 mutations in Ohtahara Syndrome patients were located in the linker regions between the two transmembrane regions, which is known to be required for fast inactivation of sodium channels.
In conclusion, this study has established that certain de novo mutations in SCN2A are associated with severe early onset epilepsies. Additional animal studies are needed to validate the link between the mutation site and severity of epileptic phenotypes. Results of this study are expected to have limited impact on the current EOEE treatment regimen. However, in the future, if they are confirmed, they have the potential to be developed into a useful diagnostic tool and serve as a new therapeutic target.
- Nakamura et al., Neurology, 2013, Sep 10:81(11): 992-8.
- Buchhalter, Epilepsy Currents, 2014, 14 (5): 253-254.
- More information on Ohtahara syndrome and a related non-profit organization (Aaron's Ohtahara Foundation)