Human Molecular Genetics Advance Access originally published online on February 26, 2007
Human Molecular Genetics 2007 16(8):900-906; doi:10.1093/hmg/ddm034
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Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred
1 Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097 CNRS, Université de Nice Sophia Antipolis, France, 2 Fédération de Neurophysiologie Clinique and Centre de Référence des Canalopathies Musculaires, Pitié-Salpêtrière Hospital, Paris, France, 3 Department of Pediatrics, Montluçon Hospital, Montluçon, France and 4 Neurology Department, Rennes Hospital, Rennes, France
* To whom correspondence should be addressed at: Université de Nice Sophia Antipolis, UMR 6097 CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, 660 Route des Lucioles, Sophia-Antipolis 06560, Valbonne, France. Tel: +33 493957741; Fax: +33 493957708; Email: bendahhou{at}ipmc.cnrs.fr
Received January 10, 2007; Revised January 10, 2007; Accepted February 15, 2007
Periodic paralysis, cardiac arrhythmia and bone features are the hallmark of Andersen's syndrome (AS), a rare disorder caused by mutations in the KCNJ2 gene that encodes for the inward rectifier K+-channel Kir2.1. Rest following strenuous physical activity, carbohydrate ingestion, emotional stress and exposure to cold are the precipitating triggers. Most of the mutations act in a dominant-negative fashion, either through a trafficking dysfunction or through Kir2.1-phosphatidyl inositol bisphosphate binding defect. We have identified two families that were diagnosed with periodic paralysis and cardiac abnormalities, but only discrete development features. The proband in one of the two families reported having his symptoms occurring twice within the day following corticosteroids ingestion, and alleviated after stopping the corticosteroid treatment. Electromyographic evaluations pointed out to a typical hypokalemic periodic paralysis pattern. Molecular screening of the KCNJ2 gene identified two mutations leading to C54F and T305P substitutions in the Kir2.1 protein. Functional expression in mammalian cells revealed a loss-of-function of the mutated channels and a dominant-negative effect when both mutants and wild-type channels are present in the same cell. However, channel trafficking and assembly are not affected. Substitutions at these residues may interfere with phosphatidyl inositol bisphosphate binding to Kir2.1 channels. Sensitivity of our patients to multiple corticosteroid administrations shows that care must be taken in the use of such treatments in AS patients. Taken together, our data suggest the inclusion of the KCNJ2 gene in the molecular screening of patients with periodic paralysis, even when the classical AS dysmorphic features are not present.
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