A novel SCN4A mutation causing myotonia aggravated by cold and potassium.

The single strand conformation polymorphism (SSCP) technique was used to screen genomic DNA of a family with myotonia aggravated by cold, potassium loading and suxamethonium, but without muscle weakness. An aberrant band was found in exon 24 of SCN4A, the gene encoding the adult skeletal muscle sodium channel alpha-subunit. DNA sequencing led to the detection of a G-to-A transition of cDNA nucleotide 4765 predicting a substitution of methionine for valine at position 1589 of the protein sequence. This amino acid is located within transmembrane segment S6 of channel repeat IV close to the cytoplasmic surface, a region which is supposed to act as acceptor of the inactivation gate of the channel. Four lines of evidence indicate that this mutation causes the disease: (i) the transition was only found for affected family members; (ii) no mutations were found in all other SCN4A exons; (iii) the affected gene region is conserved among various species; and (iv) an increase in the number of non-inactivating sodium channels had been revealed in earlier electrophysiological studies on an excised muscle specimen from the index patient. In addition, the close-by occurring substitution of valine for methionine at position 1592 known to cause hyperkalemic periodic paralysis was deduced for six families with the myotonic, non-dystrophic form of this disease.