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A mutation of SCN1B associated with GEFS+ causes functional and maturation defects of the voltage‐dependent sodium channel
Author(s) -
Baroni Debora,
Picco Cristiana,
Moran Oscar
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23589
Subject(s) - sodium channel , biology , protein subunit , mutation , g alpha subunit , gating , microbiology and biotechnology , hek 293 cells , heterologous expression , scn3a , biophysics , genetics , sodium , chemistry , gene , recombinant dna , organic chemistry
Voltage‐dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore‐forming α‐subunit, and one or more auxiliary β subunits. Mutation p.Asp25Asn (D25N; c.73G > A) of the β1 subunit, coded by the gene SCN1B , has been reported in a patient with generalized epilepsy with febrile seizure plus type 1 (GEFS+). In human embryonic kidney 293 (HEK) cells, the heterologous coexpression of D25N‐β1 subunit with Nav1.2, Nav1.4, and Nav1.5 α subunits, representative of brain, skeletal muscle, and heart voltage gated sodium channels, determines a reduced sodium channel functional expression and a negative shift of the activation and inactivation steady state curves. The D25N mutation of the β1 subunit causes a maturation (glycosylation) defect of the protein, leading to a reduced targeting to the plasma membrane. Also the β1‐dependent gating properties of the sodium channels are abolished by the mutation, suggesting that D25N is no more able to interact with the α subunit. Our work underscores the role played by the β1 subunit, highlighting how a defective interaction between the sodium channel constituents could lead to a disabling pathological condition, and opens the possibility to design a mutation‐specific GEFS+ treatment based on protein maturation.