Potassium Channel Subunit Kir4.1 Mutated in Paroxysmal Kinesigenic Dyskinesia: Screening of an Italian Cohort

Abstract

The missing heritability of paroxysmal kinesigenic dyskinesia (PKD) may be explained by genetic heterogeneity with unexplored contributions of genes other than PRRT2 or TMEM151A. Preliminary data published by Wirth et al¹ suggested a causal link between recessive and dominant variants in KCNJ10 and PKD in four French pedigrees. More recently, Li et al² reported on the identification of dominant KCNJ10 variants in Chinese patients with PKD. In 168 exome-sequenced families, they discovered eight heterozygous missense KCNJ10 variants in 11 patients presenting attacks of predominantly dystonic character.² KCNJ10 encodes the inward-rectifying potassium (K+) channel Kir4.1, a master regulator of K⁺ concentrations in the brain. Kir4.1 channels are enriched in neuroglia, where they contribute to cell-volume maintenance and neurotransmission.² Downregulation of Kir4.1 is believed to result in neural death,³ whereas KCNJ10 biallelic loss-of-function mutations produce a monogenic disorder with ataxia, seizures, and deafness (EAST/SeSAME syndrome).⁴ Functional studies of the Kir4.1 mutants detected by Li et al² showed loss of channel activity consistent with haploinsufficiency. Despite these results, the role of KCNJ10 variants in different PKD populations is not well understood.

To replicate the newly proposed gene–phenotype relationship, we screened KCNJ10 for nonsynonymous variants in exome data of 25 simplex PKD cases and one kindred with three patients from Italy. Genetic analyses were performed as detailed elsewhere⁵; PRRT2, TMEM151A, and other established PKD gene-related mutations had been excluded. All patients were diagnosed according to consensus criteria by movement disorder experts at the Neurological Institute “Besta” (Milan, Italy). Written informed consent for study participation was obtained. We singled out a heterozygous c.511C>T, p.Arg171Trp substitution, carried by a 27-year-old man with a 13-year history of PKD. Strikingly, the exact same KCNJ10 variant was described in one of the families from Li et al² (PKD123). Furthermore, an alternative amino acid change at Arg171 has previously been defined as a cause of EAST/SeSAME syndrome,⁶ indicating that this residue might represent a disease mutation hot spot. Electrophysiological characterization of p.Arg171Trp demonstrated an ~90% reduction of K⁺ currents compared with wild type, indicative of pathological Kir4.1 dysfunction.² We classified c.511C>T, p.Arg171Trp as “likely pathogenic” (PS3 + PM1 + PM2 + PP3 according to American College of Medical Genetics and Genomics standards⁷). Our KCNJ10 p.Arg171Trp-positive patient displayed brief dystonic episodes (5–10 s) triggered by sudden movements. The paroxysms involved the mouth and upper and lower limbs sequentially but on alternate sides; frequency was variable, from daily to monthly, and aggravated by stress. His neurological examination, interictal electroencephalography, and brain magnetic resonance imaging were normal. The phenotype closely matched with the one reported for “PKD123” in Li et al² (Table 1); both cases also had a negative family history, indicating that KCNJ10 variants are associated with incomplete penetrance, similar to PRRT2-related PKD. This conjecture is supported by the fact that p.Arg171Trp is seen (at extremely low frequency) in the gnomAD database.

Taken together, we provide additional evidence for the implication of mutant Kir4.1 in the etiology of PKD by establishing variant recurrence in independent populations of affected subjects. The study of Kir4.1 aberrations in PKD may offer unique insights into unanticipated roles of glial cells in the pathogenesis of abnormal movements.

Nothing to report.

Giovanna Zorzi: study design and concept, acquisition of data, clinical examination, analysis and interpretation of data, and revision of manuscript for critical intellectual content. Federica Zibordi: acquisition of data, clinical examination, and revision of manuscript for critical intellectual content. Ugo Sorrentino: acquisition of data and revision of manuscript for critical intellectual content. Holger Prokisch: acquisition of data and revision of manuscript for critical intellectual content. Barbara Garavaglia: study design and concept, study supervision, and analysis and interpretation of data. Michael Zech: study design and concept, study supervision, analysis and interpretation of data, and writing of the manuscript.