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dc.contributor.authorHasan, Sonia M.-
dc.contributor.authorBalobaid, Ameera-
dc.contributor.authorGrottesi, Alessandro-
dc.contributor.authorDabbagh, Omar-
dc.contributor.authorCenciarini, Marta-
dc.contributor.authorRawashdeh, Rifaat-
dc.contributor.authorAl-Sagheir, Afaf-
dc.contributor.authorBove, Cecilia-
dc.contributor.authorMacchioni, Lara-
dc.contributor.authorPessia, Mauro-
dc.contributor.authorAl-Owain, Mohammed A.-
dc.contributor.authorD'Adamo, Maria Cristina-
dc.identifier.citationHasan, S., Balobaid, A., Grottesi, A., Dabbagh, O., Cenciarini, M., Rawashdeh, R.,...D’Adamo, M.C. (2017). Lethal digenic mutations in the K+ channels Kir4. 1 (KCNJ10) and SLACK (KCNT1) associated with severe-disabling seizures and neurodevelopmental delay. Journal of Neurophysiology, 118(4), 2402-2411.en_GB
dc.description.abstractA 2-yr-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 the KCNJ10gene that encodes for the inward-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 current, whereas currents from oocytes expressing the mutation were reduced, remarkably. 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 coexisting mutation in SLACK channels that results in a fatal disease.en_GB
dc.publisherAmerican Psychological Associationen_GB
dc.subjectAtaxia -- Genetic aspectsen_GB
dc.subjectPotassium channelsen_GB
dc.titleLethal digenic mutations in the K+ 1 channels Kir4.1 (KCNJ10) and SLACK 2 (KCNT1) associated with severe-disabling seizures and neurodevelopmental delayen_GB
dc.rights.holderThe copyright of this work belongs to the author(s)/publisher. The rights of this work are as defined by the appropriate Copyright Legislation or as modified by any successive legislation. Users may access this work and can make use of the information contained in accordance with the Copyright Legislation provided that the author must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the prior permission of the copyright holder.en_GB
dc.publication.titleJournal of Neurophysiologyen_GB
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