Molecular characteristics
KCNA4, Kv1.4 or HPCN2 (Potassium Voltage-Gated Channel Subfamily A Member 4) gene is located at 11p14.1. According to Ensembl, the gene has two splice variants (one of which does not produce any protein). The main transcript generates a 653 amino acid long protein (CCDS:41629; UniProt:P22459; NP_002224). The gene has 113 orthologues, 31 paralogues and is a member of potassium voltage-gated channel family. The protein mainly localizes to plasma membrane and is also found in nucleus and endoplasmic reticulum. The gene expression is somewhat ubiquitous but highly expressed in nervous system especially in hippocampus, cortex, basal ganglia, and spinal cord. Other tissues and organs include heart, muscle, colon, adipocyte, kidney, glands, skin, and bladder.
Initial genetic study
Al-Owain et al. (2013) reported a consanguineous family with four affected siblings (three girls and one boy) with a novel syndrome of abnormal striatum and congenital cataract involving the lens and the basal ganglia. The syndrome was presented with cognitive impairment, microcephaly, striatal abnormalities, congenital cataract, and attention deficit hyperactivity disorder (ADHD). The neurological phenotype seen in the patients was very slowly progressive. Using 10K single-nucleotide polymorphism (SNP) microarray genotyping linkage analysis was performed yielding a 45.9 Megabases region with a 4.2353 logarithm of the odds (LOD) score on chromosome 11. The patients were free from any chromosomal abnormalities that was interrogated using Affymetrix’s genome-wide human SNP array 6.0 assays. Numerous genes located in the linkage interval were screened using Sanger sequencing techniques and such efforts did not result in any positive results.
Follow-up study
Further genetic studies were performed on the same family using whole exome sequencing and iterative filtering coupled with autozygosity mapping and linkage analysis. This study identified a missense mutation in KCNA4. A functional study was performed using two-electrode voltage-clamp recording (Kaya et al. 2016).
Mutations and pathophysiology
Kaya et al. (2016) identified a missense mutation (KCNA4: NM_002233:exon2:c.G266A:p.R89Q) in “potassium voltage-gated channel subfamily A member 4” also known as “voltage gated potassium channel subunit KV1.4” in a large consanguineous family with four affected siblings. Currently there are only four patients reported from Saudi Arabia which creates an apparent lack of information about the likely mutations and phenotypic correlation between the site of mutation and the clinical expressivity. However, physiological studies performed on Xenopus oocytes that were injected with human Kv1.4 wild-type mRNA (R89Q and WT/R89Q channels) suggest that the mutation site suppresses current amplitude in the tested cells in comparison to those of wild type cells. Moreover, using the same approach, co-expression of the wild type and mutant mRNAs in the Xenopus oocytes also resulted in a mean current amplitude that was significantly different from that of the wild type. The pathogenic mechanism underlying the syndrome is not well-established and needs further studies as well as newly discovered cases and their correlation to the novel mutations.