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J Neurophysiol. July 26, 2017; jn.00284.2017.

Lethal digenic mutations in the K(+) channels Kir4.1 (KCNJ10) and SLACK (KCNT1) associated with severe-disabling seizures and neurodevelopmental delay.

Hasan SM , Balobaid A , Grottesi A , Dabbagh O , Cenciarini M , Rawashdeh R , Al-Sagheir A , Bove C , Macchioni L , Pessia M , Al-Owain M , D'Adamo MC .

A 2-year-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia and tonic-clonic seizures that caused the death of the patient. Targeted and whole-exome sequencing revealed two heterozygous missense variants: a novel mutation in KCNJ10 gene that encodes for the inwardly-rectifying K(+) channel Kir4.1 and another previously characterized mutation in KCNT1 that encodes for the Na(+)-activated K(+) channel known as Slo2.2 or SLACK. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4.1 mutation. The mutant and wild-type KCNJ10 constructs were generated and heterologously expressed in Xenopus laevis oocytes, and whole-cell K(+) currents were measured using the two-electrode voltage-clamp technique. The KCNJ10 mutation c.652C>T resulted in a p.L218F substitution at a highly conserved residue site. Wild-type KCNJ10 expression yielded robust Kir currents, while currents from oocytes expressing the mutation were reduced. Western Blot analysis revealed reduced protein expression by the mutation. Kir5.1 subunits display selective heteromultimerization with Kir4.1 constituting channels with unique kinetics. The effect of the mutation on Kir4.1/5.1 channel activity was twofold: a reduction in current amplitudes and an increase in the pH-dependent inhibition. We thus report a novel loss-of-function mutation in Kir4.1 found in a patient with a co-exiting mutation in SLACK channels that results in a fatal disease.

PubMed ID: 28747464
Article link: J Neurophysiol.

Genes referenced: kcnj10 kcnt1

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