NKX2.5 mutations in patients with congenital heart disease.
NKX2.5 mutations in patients with congenital heart disease.
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DOI：
10.1016/j.accreview.2003.12.072
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发表时间：
2004-02
影响因子：
24
通讯作者：
D. McElhinney;E. Geiger;J. Blinder;D. Benson;E. Goldmuntz
中科院分区：
文献类型：
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作者：
D. McElhinney;E. Geiger;J. Blinder;D. Benson;E. Goldmuntz
本研究的目的是评估NKX2.5突变在特定心血管畸形中的频率，并研究NKX2.5突变个体的基因型-表型相关性。背景最近的报道暗示转录因子NKX2.5的突变是各种先天性心脏病（CHD）的原因。方法我们检测了608例前瞻性招募的圆锥动脉干异常患者（n = 10）的基因组脱氧核糖核酸。结果在608例患者中有18例（3%）发现了NKX2.5编码区的12种不同突变，其中包括201例法洛四联症患者中的9例（4%），3/71例（4%）继发性ASD患者，动脉干、右心室双出口、大动脉L型转位、主动脉弓中断、左心发育不良综合征和主动脉缩窄各1例，但无D型大动脉转位（n = 86）或瓣膜性主动脉狭窄（n = 21）患者。其中11个突变是改变氨基酸的错义核苷酸取代或缺失，其中一个被预测会导致翻译提前终止。没有一个突变发生在同源结构域中。18例NKX 2. 5突变患者中16例无先天性心血管畸形家族史，1例有一度房室传导阻滞。在这项研究中发现的大多数突变是错义的，在同源结构域之外，与房室传导阻滞无关。这些发现提示NKX2.5基因非同源结构域突变可能在人类心脏结构缺陷的发生中起重要作用。
ObjectivesThe purpose of this study was to estimate the frequency ofNKX2.5mutations in specific cardiovascular anomalies and investigate genotype-phenotype correlations in individuals withNKX2.5mutations.BackgroundRecent reports have implicated mutations in the transcription factorNKX2.5as a cause of various congenital heart defects (CHD).MethodsWe tested genomic deoxyribonucleic acid from 608 prospectively recruited patients with conotruncal anomalies (n = 370), left-sided lesions (n = 160), secundum atrial septal defect (ASD) (n = 71), and Ebstein's malformation (n = 7) forNKX2.5mutations.ResultsTwelve distinct mutations in theNKX2.5coding region were identified in 18 of 608 patients (3%), including 9 of 201 (4%) with tetralogy of Fallot, 3 of 71 (4%) with a secundum ASD, one each with truncus arteriosus, double-outlet right ventricle, L-transposition of the great arteries, interrupted aortic arch, hypoplastic left heart syndrome, and aortic coarctation, but in no patients with D-transposition of the great arteries (n = 86) or valvar aortic stenosis (n = 21). Eleven of the mutations were amino acid-altering missense nucleotide substitutions or deletions, and one was predicted to cause premature termination of translation. None of the mutations were in the homeodomain. Sixteen of the 18 individuals withNKX2.5mutations in this study had no family history of congenital cardiovascular anomalies, and one had first-degree atrioventricular (AV) block.ConclusionsNKX2.5mutations occur in a small percentage of patients with various CHD. Most of the mutations identified in this study were missense, outside the homeodomain, and not associated with AV block. These findings suggest thatNKX2.5mutations in non-homeodomain regions may be important in the development of human structural cardiac defects.