Spectrum of mutations in long-QT syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2
Spectrum of mutations in long-QT syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2
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DOI：
10.1161/01.cir.102.10.1178
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发表时间：
2000-09-05
期刊：
影响因子：
37.8
通讯作者：
Keating, MT
中科院分区：
文献类型：
--
作者：
Splawski, I;Shen, JX;Keating, MT
长QT综合征（LQTS）是一种以心电图QT间期延长为特征的心血管疾病，伴有晕厥、癫痫发作和猝死。五个基因与Romano-Ward综合征（LQTS的常染色体显性形式）有关：KVLQT 1、HERG、SCN 5A、KCNE 1和KCNE 2。KVLQT 1和KCNE 1突变也会导致Jervell和Lange-Nielsen综合征，一种与耳聋相关的LQTS形式，一种常染色体隐性遗传的表型异常fashion.Methods和Results-We使用突变分析来筛选262个不相关的LQTS个体的5个定义的基因突变。除了我们以前报道的43个突变外，我们还确定了134个突变。80个突变是新的。结论KVLQT 1（42%）和HERG（45%）占已鉴定突变的87%，SCN 5A（8%）、KCNE 1（3%）和KCNE 2（2%）占其他突变的13%。错义突变最常见（72%），其次是移码突变（10%），框内缺失，无义突变和剪接位点突变（各5%至7%）。大多数突变位于细胞内（52%）和跨膜（30%）结构域，12%被发现在孔和6%的细胞外段。在大多数情况下（78%），在单个家庭或个体中发现突变。
Background-Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.Methods and Results-We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals).Conclusions KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.