التفاصيل البيبلوغرافية
| العنوان: |
A KCNC1‐related neurological disorder due to gain of Kv3.1 function. |
| المؤلفون: |
Clatot, Jerome, Ginn, Natalie, Costain, Gregory, Goldberg, Ethan M. |
| المصدر: |
Annals of Clinical & Translational Neurology; Jan2023, Vol. 10 Issue 1, p111-117, 7p |
| مصطلحات موضوعية: |
NEUROLOGICAL disorders, MYOCLONUS, GENETIC variation, MISSENSE mutation, EPILEPSY, INTELLECTUAL disabilities, DEVELOPMENTAL delay |
| مستخلص: |
Objective: To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage‐gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. Methods: We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole‐cell voltage clamp electrophysiological recording of wild‐type versus variants in a heterologous mammalian expression system. Results: We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. Interpretation: Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3‐expressing high frequency‐ firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical‐genetic syndrome within the spectrum of KCNC1‐related neurological disorders. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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