HsaEX0056544 @ hg19

HsaEX0056544 and HsaEX0056545 are mutually exclusive with HsaEX0056544 being predominantly fetal/neonatal and HsaEX0056545 being predominantly adult. Neonatal (contains HsaEX0056544) and adult (contains HsaEX0056545) splice forms of NaV1.2 with a Benign familial neonatal?infantile seizures (BFNIS) mutation (L1563V) were examined in human embryonic kidney cells. Computer modeling revealed that neonatal channels are less excitable than adult channels. Introduction of the mutation increased excitability in the neonatal channels to a level similar to adult channels. By contrast, the mutation did not affect the adult channel variant. This ?adult-like? increased excitability is likely to be the mechanism underlying BFNIS in infants with this mutation.

The authors engineered five EOEE-associated NaV1.2 variants (T236S, E999K, S1336Y, T1623N, and R1882Q) into the adult (HsaEX0056545) and neonatal (HsaEX0056544) splice isoforms of NaV1.2 and performed whole-cell voltage clamp to elucidate their functional properties. All variants exhibited functional defects that could enhance neuronal excitability. Three of the five variants (T236S, E999K, and S1336Y) exhibited greater dysfunction in the neonatal isoform compared with those observed in the adult isoform. Computational modeling of a developing cortical pyramidal neuron indicated that T236S, E999K, S1336Y, and R1882Q showed hyperexcitability preferentially in immature neurons.

Mice expressing only the ?adult? NaV1.2 isoform (containing HsaEX0056545) were generated (NaV1.2adult), and the firing properties of pyramidal cortical neurons, as well as seizure susceptibility, were compared between the NaV1.2adult and wild-type (WT) mice at postnatal day 3 (P3), when the ?neonatal? isoform (containing HsaEX0056544) represents 65% of the WT NaV1.2.There were significant increases in action potential firing in NaV1.2adult neurons and in seizure susceptibility of NaV1.2adult mice. At postnatal day 15 (P15), when 17% of the WT NaV1.2 is ?neonatal?, the firing properties of NaV1.2adult and WT neurons converged. However, inhibitory postsynaptic currents in NaV1.2adult neurons were larger and the expression level of Scn2a mRNA was 24% lower compared with the WT. The enhanced seizure susceptibility of the NaV1.2adult mice persisted into adult age. The adult NaV1.2adult mice also exhibited greater risk-taking behaviour.