Article Text
Abstract
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.
- CHANNELS
- NEUROMUSCULAR
- MUSCLE DISEASE
- NEUROGENETICS
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/
Statistics from Altmetric.com
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
- Adobe PDF - jnnp-2014-309293-supplementary_file_S1.pdf