Davies N P, Imbrici P, Fialho D, Herd C, Bilsland L G, Weber A, Mueller R, Hilton-Jones D, Ealing J, Boothman B R, Giunti P, Parsons L M, Thomas M, Manzur A Y, Jurkat-Rott K, Lehmann-Horn F, Chinnery P F, Rose M, Kullmann D M, Hanna M G
Muscle and Nerve Centre, Queen Elizabeth Hospital, University of Birmingham NHS Trust, UK.
Neurology. 2005 Oct 11;65(7):1083-9. doi: 10.1212/01.wnl.0000178888.03767.74.
To evaluate clinical, genetic, and electrophysiologic features of patients with Andersen-Tawil syndrome (ATS) in the United Kingdom.
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.
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.
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.
评估英国安德森-陶威尔综合征（ATS）患者的临床、遗传和电生理特征。
对11个疑似患有ATS的家庭进行了临床和神经生理学评估。通过对KCNJ2整个编码区进行直接DNA测序，对每个先证者进行分子遗传学分析。对照样本通过直接DNA测序进行筛查。在卵母细胞表达系统中研究了几种新突变的电生理后果。
所有11个ATS家庭的KCNJ2均存在致病突变，其中6种突变以前未报道过。观察到一些不寻常的临床特征，包括肾小管缺陷、中枢神经系统受累以及牙齿和发声异常。表达了5种突变（T75M、D78G、R82Q、L217P和G300D），单独表达时所有这些突变均导致通道无功能，与野生型（WT）KCNJ2共表达显示出显性负效应。
鉴定出KCNJ2中的6种新致病突变，其中一种位于磷脂酰肌醇-4,5-二磷酸（PIP2）结合位点。分子表达研究表明，其中5种突变对野生型等位基因产生显性负效应。在英国，KCNJ2突变是ATS的重要病因。
