Background Voltage-gated potassium channels are highly diverse proteins representing the most complex class of voltage-gated ion channels from structural and functional perspectives. Deficiency of these channels usually results in various human disorders.
Objectives To describe a novel autosomal recessive syndrome associated with KCNA4 deficiency leading to congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder.
Methods We used SNP arrays, linkage analyses, autozygosity mapping, whole-exome sequencing, RT-PCR and two-electrode voltage-clamp recording.
Results We identified a missense variant (p.Arg89Gln) in KCNA4 in four patients from a consanguineous family manifesting a novel syndrome of congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder. The variant was fully segregated with the disease and absent in 747 ethnically matched exomes. Xenopus oocytes were injected with human Kv1.4 wild-type mRNA, R89Q and WT/R89Q channels. The wild type had mean current amplitude that was significantly greater than those recorded from the cells expressing the same amount of mutant mRNA. Co-expression of the wild type and mutant mRNAs resulted in mean current amplitude that was significantly different from that of the wild type. RT-PCR indicated that KCNA4 is present in mouse brain, lens and retina. KCNA4 interacts with several molecules including synaptotagmin I, DLG1 and DLG2. The channel co-localises with cholinergic amacrine and rod bipolar cells in rats and is widely distributed in the central nervous system. Based on previous studies, the channel is highly expressed in outer retina, rod inner segments, hippocampus and concentrated in axonal membranes.
Conclusion KCNA4 (Kv1.4) is implicated in a novel syndrome characterised by striatal thinning, congenital cataract and attention deficit hyperactivity disorder. Our study highlights potassium channels' role in ocular and neuronal genetics.
- Potassium Channel
Statistics from Altmetric.com
MA, MCD and AA are contributed equally.
Contributors NK conceived and designed the experiments. MAld, SH, AA-B, MCD, FBA, RA, MA, DM, BA, RK, JA-Z, FSB, EN, AQ, FA, MM and OMM performed the experiments. NK, DC, MP, DM, BM, TFP and MA-O analysed the data. NK and DC wrote the paper. DC, MA-O, MP and TFP revised the manuscript. MA collected samples, handled biopsies, undertook patient care and management, collected clinical data and delineated the patients’ phenotype. OMM re-reviewed the patients’ charts.
Funding This research was conducted through intramural funds provided by King Faisal Specialist Hospital and Research Centre (KFSHRC-RAC: 2120022) and National Plan for Science, Technology and Innovation Programme under King Abdulaziz City for Science and Technology (NSTIP/KACST) for supporting NK (11-BIO2221-20) and DC (11-BIO2072-20).
Competing interests None declared.
Patient consent Obtained.
Ethics approval King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.