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CLCN1 Myotonia congenita mutation with a variable pattern of inheritance suggests a novel mechanism of dominant myotonia
Author(s) -
Gaitánpeñas Héctor,
ArmandUgón Mercedes,
Macaya Alfons,
Estévez Raúl
Publication year - 2018
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.26098
Subject(s) - myotonia congenita , missense mutation , myotonia , xenopus , mutant , mutation , genetics , biology , microbiology and biotechnology , medicine , endocrinology , gene , myotonic dystrophy
: Mutations in CLCN1 cause recessive or dominant forms of myotonia congenita (MC). Some mutations have been found to exhibit both patterns of inheritance but the mechanism explaining this behavior is unknown. Methods : A known recessive missense mutation, A493E, was identified in a family with dominant MC. The mutant p.A493E alone or in co‐expression with wild‐type (WT) ClC‐1 was expressed in Xenopus oocytes. Currents were measured and biochemical assays were performed. Results : The mutant showed no significant activity and reduced total and plasma membrane (PM) protein levels. Co‐expression with the mutant reduced the activity and PM levels of an engineered lower expression variant of ClC‐1, whereas no effect was observed on a higher expression variant. Discussion : Our results suggest that the dominant effect of some CLCN1 mutations showing recessive or dominant inheritance patterns may be due to a dose‐dependent defect in PM delivery of the WT channel. Muscle Nerve 58 : 157–160, 2018