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Andersen's syndrome is a rare syndrome involving periodic paralysis, cardiac arrhythmias, and dysmorphic features. In this study, we linked an Andersen's gene to markers on chromosome 17q23 (maximum D17S949 LOD ฯญ 3.23 at ฯญ 0) near the inward rectifying potassium channel gene KCNJ2, encoding Kir2.1. Sequencing KCNJ2 in the linkage family identified the mutation D71V in the N terminus of the protein. Sequencing of additional unrelated Andersen's patients revealed a total of 12 different mutations occurring in 16 of 22 Andersen's probands. Expression of eight of these mutations in Xenopus oocytes revealed a range of functional consequences from haploinsufficiency to a complete dominant negative effect in Kir2.1 current as assayed by voltage-clamp studies. Mammalian expression with GFP tagged proteins suggests that the defect does not result from altered trafficking but, rather, from altered physiological properties of the mutant channels. We conclude from these studies that mutations in Kir2.1 cause Andersen's syndrome. Our findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart. Further studies to define the role of this channel in development are under way.
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