Deletion of Kv10.2 Causes Abnormal Dendritic Arborization and Epilepsy Susceptibility

Liu, Yamei; Tang, Yunfei; Yan, Jin; Du, Dongshu; Yang, Yang; Chen, Fuxue

doi:10.1007/s11064-020-03143-7

Cited by 2 publications

(1 citation statement)

References 32 publications

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“…It is not striking that either loss or gain of function in a protein channel leads to a dysfunction of the channel, as the activation dynamics are anyhow affected. Recently, Kv10.2 deletion was shown to increase epilepsy susceptibility in a rat model, the authors proposing a role for Kv10.2 in the development of epileptic disorders [ 42 ]. Our results also further support suggestions that the chromosomal region around 14q23.2, where KCNH5 is localised, might be a 'hot spot' for neurological diseases.…”

Section: Discussionmentioning

confidence: 99%

A novel loss-of-function mutation of the voltage-gated potassium channel Kv10.2 involved in epilepsy and autism

Galán-Vidal

Socuéllamos

Baena-Nuevo

et al. 2022

Orphanet J Rare Dis

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Background Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiological defects and the appropriate treatments. Results We have isolated and cultured primary cells from the skin of a patient with combined epilepsy and autism syndrome. A mutation in the potassium channel protein Kv10.2 was identified. We have characterised the alteration of the mutant channel and found that it causes loss of function (LOF). Primary cells from the skin displayed a very striking growth defect and increased differentiation. In vitro treatment with various carbonic anhydrase inhibitors with various degrees of specificity for potassium channels, (Brinzolamide, Acetazolamide, Retigabine) restored the activation capacity of the mutated channel. Interestingly, the drugs also recovered in vitro the expansion capacity of the mutated skin cells. Furthermore, treatment with Acetazolamide clearly improved the patient regarding epilepsy and cognitive skills. When the treatment was temporarily halted the syndrome worsened again. Conclusions By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial. The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases.

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Section: Discussionmentioning

confidence: 99%