Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients.
artículo original
Date
2021Author
Brenes García, Oscar Gerardo
Barbieri, Raffaella
Vásquez Cerdas, Melissa
Vindas Smith, Rebeca
Roig Fernández Jeffry
Romero Vásquez, Adarli
del Valle Carazo, Gerardo
Bermúdez Guzmán, Luis
Bertelli, Sara
Pusch, Michael
Morales Montero, Fernando
Metadata
Show full item recordAbstract
Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1
chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe
a family with members diagnosed with Thomsen’s disease. One novel mutation (p.W322*) in
CLCN1 and one undescribed mutation (p.R1463H) in SCN4A are segregating in this family. The
CLCN1-p.W322* was also found in an unrelated family, in compound heterozygosity with the known
CLCN1-p.G355R mutation. One reported mutation, SCN4A-p.T1313M, was found in a third family.
Both CLCN1 mutations exhibited loss-of-function: CLCN1-p.W322* probably leads to a non-viable
truncated protein; for CLCN1-p.G355R, we predict structural damage, triggering important steric
clashes. The SCN4A-p.R1463H produced a positive shift in the steady-state inactivation increasing
window currents and a faster recovery from inactivation. These gain-of-function effects are probably
due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD)
IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M
induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that
CLCN1-p.W322* and SCN4A-p.R1463H mutations can act alone or in combination as inducers of
myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to
provide accurate genetic counseling and management of patients.