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Andersen–Tawil syndrome

New potassium channel mutations and possible phenotypic variation

From the Muscle and Nerve Centre (Dr. Davies), Queen Elizabeth Hospital, University of Birmingham NHS Trust, UK; Institute of Neurology (Drs. Imbrici, Fialho, Giunti, Kullmann, and Hanna, C. Herd, and L.G. Bilsland), Queen Square, London, UK; Institute of Human Genetics (Dr. Weber), International Centre for Life, Newcastle, UK; Department of Clinical Genetics (Dr. Mueller), St. James's University Hospital, Leeds, UK; Department of Neurology (Dr. Hilton-Jones), Radcliffe Infirmary, Oxford, UK; Department of Neurology (Drs. Ealing and Boothman), Royal Preston Hospital, UK; Department of Neurology (Dr. Parsons), St. Alban's Hospital, Hertfordshire, UK; Department of Neurology (Dr. Thomas), Southern General Hospital, Glasgow, UK; Dubowitz Neuromuscular Centre (Dr. Manzur), Imperial College, London, UK; Department of Neurology (Dr. Chinnery), Newcastle Royal Infirmary, UK; and Department of Neurology (Dr. Rose), King's College Hospital, London, UK; and Department of Physiology (Drs. Jurkat-Rott and Lehmann-Horn), Ulm University, Germany.

Address correspondence and reprint requests to Dr Hanna, Centre for Neuromuscular Disease, Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK; e-mail: m.hanna{at}ion.ucl.ac.uk

Objective: To evaluate clinical, genetic, and electrophysiologic features of patients with Andersen-Tawil syndrome (ATS) in the United Kingdom.

Methods: Clinical and neurophysiologic evaluation was conducted of 11 families suspected to have ATS. Molecular genetic analysis of each proband was performed by direct DNA sequencing of the entire coding region of KCNJ2. Control samples were screened by direct DNA sequencing. The electrophysiologic consequences of several new mutations were studied in an oocyte expression system.

Results: All 11 ATS families harbored pathogenic mutations in KCNJ2 with six mutations not previously reported. Some unusual clinical features including renal tubular defect, CNS involvement, and dental and phonation abnormalities were observed. Five mutations (T75M, D78G, R82Q, L217P, and G300D) were expressed, all of which resulted in nonfunctional channels when expressed alone, and co-expression with wild-type (WT) KCNJ2 demonstrated a dominant negative effect.

Conclusion: Six new disease-causing mutations in KCNJ2 were identified, one of which was in a PIP₂ binding site. Molecular expression studies indicated that five of the mutations exerted a dominant negative effect on the wild-type allele. KCNJ2 mutations are an important cause of ATS in the UK.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 11 issue to find the title link for this article.

Supported by the Wellcome Trust UK, the Medical Research Council UK, NIH-CINCH grant, the Middlesex Hospital Special Trustees, and the National Specialist Commissioning Agency (NSCAG) DoH-UK.

Disclosure: The authors report no conflicts of interest.

Received June 30, 2004. Accepted in final form June 15, 2005.

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