Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome

AbstractAndersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 maximum LOD = 3.23 at θ = 0 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These 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

Andersen syndrome: an association of periodic paralysis, cardiac arrhythmia and dysmorphic abnormalities Síndrome de Andersen: uma associação de paralisia periódica com arritmia cardíaca e alterações dismórficas

Andersen syndrome (AS) is a rare disease characterized by the presence of periodic paralysis (PP), cardiac arrhythmia and dysmorphic abnormalities. We report herein the first Brazilian patient presenting AS who also had obesity, obstructive sleep apnea (OSA) and daytime sleepiness. Clinical and genetic evaluation of six family members demonstrated that four had dysmorphic abnormalities but none had PP or cardiac arrhythmia. Sequencing of KCNJ2 revealed the R218W mutation in the index patient and her 6-year-old daughter, who presented dysmorphic abnormalities (micrognathia, clinodactyly of fourth and fifth fingers, short stature) and OSA. Three relatives had clinodactyly as the only manifestation but the R218W mutation was absent, suggesting that this characteristic may be influenced by another gene. OSA accompanied by dysmorphic features may be related to AS.<br>A síndrome de Andersen (SA) é doença rara caracterizada pela presença de paralisia periódica (PP), arritmia cardíaca e anormalidades dismórficas. Relatamos o primeiro paciente brasileiro apresentando SA, e que também apresenta obesidade e apnéia obstrutiva do sono (AOS). Avaliações clínica e genética de seis familiares demonstraram que quatro apresentavam alterações dismórficas mas nenhum tinha PP ou arritmia cardíaca. O sequenciamento do gene KCNJ2 revelou a mutação R218W no paciente índex e sua filha de 6 anos, que apresentava alterações dismórficas (micrognatia, clinodactilia do quarto e quinto dedos, baixa estatura) e AOS. Três familiares tinham clinodactilia como única manifestação mas a mutação R218W estava ausente, sugerindo que esta característica seja influenciada por outro gene. A AOS associada a alterações dismórficas pode estar relacionada à SA