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Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients

OBJECTIVE: To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic periodic paralysis (TPP). METHODS: We sequenced KCNJ18 in 474 controls (400 Caucasians, 74 male Asians) and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP...

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Autores principales: Kuhn, Marius, Jurkat-Rott, Karin, Lehmann-Horn, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717442/
https://www.ncbi.nlm.nih.gov/pubmed/25882930
http://dx.doi.org/10.1136/jnnp-2014-309293
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author Kuhn, Marius
Jurkat-Rott, Karin
Lehmann-Horn, Frank
author_facet Kuhn, Marius
Jurkat-Rott, Karin
Lehmann-Horn, Frank
author_sort Kuhn, Marius
collection PubMed
description OBJECTIVE: To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic periodic paralysis (TPP). METHODS: We sequenced KCNJ18 in 474 controls (400 Caucasians, 74 male Asians) and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP without mutations in established PP genes. RESULTS: In 10 patients without TPP, we identified 9 heterozygous, novel variations (c.–3G>A, L15S, R81C, E273X, T309I, I340T, N365S, G394R, R401W) and a questionable heterozygous causative R399X stop variant. Studies on 40 relatives of these 10 patients showed that none of the variants were de novo in the patients and that R399X occurred in 3 non-affected relatives. Most affected amino acids lacked conservation and several clinically affected relatives did not carry the patient’s variant. T309I, however, could be pathogenic under the pre-requisite of strongly reduced penetrance in females. Of the controls, 17 revealed 12 novel rare variants including the heterozygous E273X stop variant in three individuals. CONCLUSIONS: Our study shows many different, rare KCNJ18 alterations in patients as well as controls. Only perhaps one meets the requirements of a disease-causing mutation. Therefore, KCNJ18 alterations are seldom pathogenic. Additional studies are required before patients with PP can be genetically diagnosed on the basis of a KCNJ18 variant alone.
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spelling pubmed-47174422016-01-28 Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients Kuhn, Marius Jurkat-Rott, Karin Lehmann-Horn, Frank J Neurol Neurosurg Psychiatry Neurogenetics OBJECTIVE: To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic periodic paralysis (TPP). METHODS: We sequenced KCNJ18 in 474 controls (400 Caucasians, 74 male Asians) and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP without mutations in established PP genes. RESULTS: In 10 patients without TPP, we identified 9 heterozygous, novel variations (c.–3G>A, L15S, R81C, E273X, T309I, I340T, N365S, G394R, R401W) and a questionable heterozygous causative R399X stop variant. Studies on 40 relatives of these 10 patients showed that none of the variants were de novo in the patients and that R399X occurred in 3 non-affected relatives. Most affected amino acids lacked conservation and several clinically affected relatives did not carry the patient’s variant. T309I, however, could be pathogenic under the pre-requisite of strongly reduced penetrance in females. Of the controls, 17 revealed 12 novel rare variants including the heterozygous E273X stop variant in three individuals. CONCLUSIONS: Our study shows many different, rare KCNJ18 alterations in patients as well as controls. Only perhaps one meets the requirements of a disease-causing mutation. Therefore, KCNJ18 alterations are seldom pathogenic. Additional studies are required before patients with PP can be genetically diagnosed on the basis of a KCNJ18 variant alone. BMJ Publishing Group 2016-01 2015-04-16 /pmc/articles/PMC4717442/ /pubmed/25882930 http://dx.doi.org/10.1136/jnnp-2014-309293 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
spellingShingle Neurogenetics
Kuhn, Marius
Jurkat-Rott, Karin
Lehmann-Horn, Frank
Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
title Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
title_full Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
title_fullStr Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
title_full_unstemmed Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
title_short Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
title_sort rare kcnj18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients
topic Neurogenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717442/
https://www.ncbi.nlm.nih.gov/pubmed/25882930
http://dx.doi.org/10.1136/jnnp-2014-309293
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