KCNJ10 encodes the inward-rectifying potassium channel (Kir4.1) that is expressed in the brain, inner ear, and kidney. Loss-of-function mutations in KCNJ10 gene cause a complex syndrome consisting of epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome). Patients with EAST/SeSAME syndrome display renal salt wasting and electrolyte imbalance that resemble the clinical features of impaired distal tubular salt transport in Gitelman’s syndrome. A key distinguishing feature between these two conditions is the additional neurological (extrarenal) manifestations found in EAST/SeSAME syndrome. Recent reports have further expanded the clinical and mutational spectrum of KCNJ10-related disorders including non-syndromic early-onset cerebellar ataxia. Here, we describe a kindred of three affected siblings with early-onset ataxia, deafness, and progressive spasticity without other prominent clinical features. By using targeted next-generation sequencing, we have identified two novel missense variants, c.488G>A (p.G163D) and c.512G>A (p.R171Q), in the KCNJ10 gene that, in compound heterozygosis, cause this distinctive EAST/SeSAME phenotype in our family. Electrophysiological characterization of these two variants confirmed their pathogenicity. When expressed in CHO cells, the R171Q mutation resulted in 50% reduction of currents compared to wild-type KCNJ10 and G163D showed a complete loss of function. Co-expression of G163D and R171Q had a more pronounced effect on currents and membrane potential than R171Q alone but less severe than single expression of G163D. Moreover, the effect of the mutations seemed less pronounced in the presence of Kir5.1 (encoded by KCNJ16), with whom the renal Kir4.1 channels form heteromers. This partial functional rescue by co-expression with Kir5.1 might explain the lack of renal symptoms in the patients. This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts of KCNJ10, a gene initially associated only with the EAST/SeSAME syndrome.
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We thank the family for its help and co-operation. We thank M. Krieger for expert assistance.
This research was funded by the Spanish Institute of Health Carlos III (ISCIII) cofunded with the European Regional Development Fund (ERDF) within the “Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020” (PI14-948 and PI17-1659 to MAMP), the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER, 06/07/0036 grant, to M-A M-P), by the Regional Government of Madrid (CAM, B2017/BMD3721) (to M-AM-P), and by the “Deutsche Forschungsgemeinschaft” (DFG, German Research Foundation), project number 387509280, SFB 1350 (to RW).
This study was designed in compliance with the tenets of the Helsinki Declaration, and patient enrolment was approved by the ethics committee of the institution. All participants provided written informed consent prior to their participation in this study.
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Morin, M., Forst, A., Pérez-Torre, P. et al. Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype. Neurogenetics (2020). https://doi.org/10.1007/s10048-020-00605-6
- SeSAME/EAST syndrome