Disease relevance of SCN1A

• Additional evidences were brought by the identification of mutations in voltage-dependent sodium channels (SCN1A, SCN1B) in a form of generalized epilepsy with febrile seizures [1].
• Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS+ [2].
• Functional expression of the SCN1B and one of the SCN1A mutations revealed defects in fast channel inactivation which are in line with previous findings on myotonia causing mutations in SCN4A, the skeletal muscle sodium channel alpha-subunit gene, all showing an impaired fast inactivation [3].
• Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+) [4].
• BACKGROUND: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+) [5].

Psychiatry related information on SCN1A

• NAC1 is increased by cocaine selectively in the nucleus accumbens, a CNS region important for drug addiction [6].
• The similar disturbance in REMS was reported not only in child patients with infantile spasms, severe myoclonic epilepsy in infancy (SMEI), severe nocturnal enuresis, and autism but also in adult patients with Parkinson's disease (PD) [7].

High impact information on SCN1A

• Here, we characterize the functional effects of three mutations in the human neuronal sodium channel alpha subunit SCN1A by heterologous expression with its known accessory subunits, beta1 and beta2, in cultured mammalian cells [8].
• Lossin and colleagues from Al George's lab report in this issue of Neuron that three missense mutations of SCN1A found in a dominant epilepsy syndrome disrupt inactivation, thereby producing small persistent inward Na(+) currents that may result in hyperexcitability and seizures [9].
• Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations [10].
• INTERPRETATION: This controlled trial shows the antiepileptic efficacy, of add-on stiripentol in children with SMEI [11].
• Our analysis reveals that NAC-1 is significantly overexpressed in ovarian serous carcinomas and several other types of carcinomas [12].

Biological context of SCN1A

• In GEFS+ families, a mutation in the voltage-gated sodium channel beta1 subunit gene (SCN1B) at chromosome 19q13.1 and two mutations of the same alpha1 subunit gene (SCN1A) at chromosome 2q24 were identified [13].
• Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS+ type 1 a mutation in the beta1-subunit gene SCN1B, and in GEFS+ type 2 two mutations within the neuronal alpha-subunit gene SCN1A [3].
• Several missense mutations of the (Na(+))-channel alpha 1 subunit (Nav1.1) gene, SCN1A were also identified in GEFS+2 families at chromosome 2q23-q24 [14].
• 3. The aim of this report is precisely to describe the phenotypes of Japanese patients with novel SCN1A mutations and to reevaluate the entity of GEFS+ [14].
• By performing an association study, we used single nucleotide polymorphisms to investigate the distribution of genotypes of SCN1A in patients with FCs [15].

Anatomical context of SCN1A

• In contrast to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only mechanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation [3].
• PCR on human x rodent somatic cell hybrids with primers derived from SCN1A localized this gene to chromosome 2 [16].
• In one of these families, direct sequencing of blood cell DNA was not sufficient to the SCN1A mutation in the transmitting asymptomatic parent who was mosaic for the mutation [17].
• Overexpression of full-length NAC-1 enhanced tumorigenicity of ovarian surface epithelial cells and NIH 3T3 cells in athymic nu/nu mice [12].
• Investigations on the general characteristics of human astrocytoma cell line NAC-1 revealed neuroblastoma growth inhibitory activity in conditioned medium [18].

Associations of SCN1A with chemical compounds

• All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A-->C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T) [19].
• We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively) [20].
• Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit [21].
• Review of the literature indicates that recurrent mutations account for 25% of SCN1A mutations in severe myoclonic epilepsy of infancy, including six sites of deamination at CpG dinucleotides [22].
• FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca(2+) channel), ATP1A2 (N(+)-K(+)-ATPase) and SCN1A (Na(+) channel) genes [23].

Other interactions of SCN1A

• We now studied the second GEFS+ mutation (T875M in SCN1A), using the highly homologous SCN4A gene (mutation T685M) [3].
• Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations [24].
• The lack of association between febrile convulsions and polymorphisms in SCN1A [15].
• Severe epilepsy, retardation, and dysmorphic features with a 2q deletion including SCN1A and SCN2A [25].
• Polymerase chain reaction was used to identify the A/G polymorphism of the SCN1A gene [15].

Analytical, diagnostic and therapeutic context of SCN1A

• Mutational screening of SCN1A and GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram [26].
• Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping [27].
• De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study [28].
• The incidence of epilepsy in relatives of patients with SMEI and absence epilepsy was increased compared with that in the control group and reached statistical significance [29].
• Both coimmunoprecipitation and double immunofluorescence staining demonstrate that NAC-1 molecules homooligomerize through the BTB/POZ domain [12].

References