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From the Department of Human Genetics and Molecular Biology (M.R. Donaldson), Howard Hughes Medical Institute and Department of Neurology (Dr. Ptácek, J.L. Jensen), and Department of Pediatric Cardiology (Dr. Tristani–Firouzi), University of Utah, Salt Lake City; Neuromuscular Disease Center (Dr. Tawil), University of Rochester School of Medicine and Dentistry, NY; Department of Pediatrics (Dr. Suarez), Mercy Children’s Hospital, Toledo, OH; Departments of Pediatrics and Biochemistry and Molecular Genetics (Dr. Wagstaff), University of Virginia Health System, Charlottesville; Department of Neurology and Research Center for Genetic Medicine (Dr. Escolar), Children’s National Medical Center, George Washington University, Washington, DC; Department of Neurology (Dr. Mozaffar), University of California, Irvine; and Department of Neurology (Dr. Fu), University of California, San Francisco; Institut de pharmacologie moléculaire et cellulaire (Dr. Bendahhou), Université de Nice, Sophia Antipolis, and INSERM U491 (Dr. Szepetowski, S. Pereira), Génétique médicale et développement, Faculté de médecine de la Timone, Marseille, France; Unidad de Genética (Dr. Cobo) and Servicio de Neurología (Dr. Poza), Hospital Donostia, San Sebastian, Spain; and Cardiological Sciences (Dr. Behr), St. George’s Hospital Medical School, London, UK.
Address correspondence and reprint requests to Dr. L.J. Ptácek, University of California San Francisco, M-798, 505 Parnassus Ave., Box 0114, San Francisco, CA 94143; e-mail: ptacek{at}itsa.uscf.edu
Background: Mutations in KCNJ2 , the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen–Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified.
Methods: Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2 . The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS.
Results: Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations (D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP2-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2 -based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males.
Conclusions: The novel mutations corresponding to residues involved in Kir2.1 channel–PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.
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