Andersen’s syndrome is a rare disorder characterised by periodic paralysis, cardiac arrhythmias and dysmorphic features. It occurs either sporadically or as an autosomal dominant disease with highly variable traits among members of the same affected family. Recently, missense mutations of KCNJ2, the gene encoding the inward rectifier potassium channel Kir2.1, were identified in Andersen’s syndrome (Plaster et al. 2001). To date twelve point mutations have been characterised, all involving residues that are highly conserved across all Kir subunits, and that lie in functionally important domains of the channel. Mutants that have been studied in heterologous expression fail to form functional channels when expressed alone, and cause variable degrees of dominant-negative effect when co-expressed with wild-type (wt) Kir2.1.

We have identified six additional mutations in British families with Andersen’s syndrome (with informed consent), in which probands presented with periodic paralysis. The mutations occur in either the N-terminus (R67W, T75M, D78G, R82Q) or the C-terminus (L217P, G300D), but none affects either the transmembrane segments or the pore-lining loop. All but one (R67W) of these mutations are previously undescribed. We injected cRNA coding for wt and/or mutant Kir2.1 into Xenopus laevis oocytes obtained using standard methods, and recorded K⁺ currents with the two electrode voltage-clamp technique. All four mutants studied (T75M, R82Q, L217P, G300D) were non-functional, and caused a complete dominant-negative suppression of channel function when co-expressed with wt. No significant functional differences were identified among the mutants.

Kir2.1 is expressed in heart, skeletal muscle and brain where it contributes to the repolarising phase of action potentials, and to stabilisation of the membrane resting potential. Reduction of Kir2.1 function is expected to increase membrane excitability, thus explaining the cardiac arrhythmias and periodic paralysis. The developmental characteristics of the Kir2.1 knockout mouse (narrowing of the maxilla and cleft of the secondary palate) are consistent with the dysmorphic features seen in many Andersen’s syndrome patients, suggesting an additional role for this channel in musculoskeletal development.