Novel KCNJ10 mutation identified in a SeSAME family compromise channel function and impairs Drosophila locomotor behavior

Deficits in the inwardly rectifying K channel, Kir4.1, cause SeSAME syndrome, autism spectrum disorders with seizures, multiple sclerosis, Huntington disease and Rett syndrome. Understanding how deficits in a single gene can accomplish such diverse neurological symptoms, requires that we know the functional role of Kir4.1 in the nervous system. We used whole exome sequencing (WES), channel physiology in patient-specific lymphoblastoid cells (LCLs) and established a Drosophila model to examine the functional effects of a KCNJ10 variant identified in SeSAME like family. WES analysis of six related affected individuals, born out of consanguineous parentage, identified KCNJ10(T290A) variant residing within a long homozygous stretch in Chr1. The membrane potential of LCLs carrying KCNJ10(T290A) variant were significantly depolarized and exhibit defects in potassium permeability, thus demonstrating a loss of function effect. Drosophila irk2 mutant, a human homolog of Kir4.1, exhibited impairment locomotion, shortened life span and age dependent degeneration of dopaminergic neurons in the adult brain. Finally, neural specific expression of either Kir4.1 or Irk2 alleviate irk2 mutant phenotypes, while the Kir4.1(T290A) and Irk2(T290A) mutant proteins failed to do so. These results imply the functional conservation of Kir4.1 across species thereby elevate the potential of using Drosophila model to improve our understanding of the SeSAME syndrome. Our results emphasize the importance of Kir4.1 in regulating extracellular K homeostasis, which is central to patterning of nervous system during development.