Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome
Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome
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DOI：
10.1159/000366274
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发表时间：
2014-01-01
影响因子：
4.7
通讯作者：
Persani, Luca
中科院分区：
文献类型：
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作者：
de Filippis, Tiziana;Marelli, Federica;Persani, Luca
目的：验证NKX2-1基因在脑-肺-甲状腺（BLT）综合征婴儿中的作用，以及出生后发病的先天性甲状腺功能减退（CH）或特发性轻度甲状腺功能减退（IMH）中甲状腺功能减退的表型变异。方法：采用病例查找法对130例CH和53例IMH患儿进行筛选。通过直接测序和多重连接依赖探针扩增分析NKX2-1基因。通过表达分析和荧光素酶生物测定对这些变异进行了体外研究。结果：发现符合BLT综合征的4例（3例CH， 1例IMH）。2例患儿出现呼吸窘迫和CH，均为野生型NKX2-1基因。其余两例表现为舞蹈性运动，未累及肺部，但甲状腺表型不同：一例有严重的CH伴舌异位，另一例有原位腺体的IMH。它们是NKX2-1新发杂合移码突变（c.177delG和c.153_166del14）的携带者。c. 177delG导致体外检测不到活性的过早截断蛋白（p.H60TfsX11）。c.153_166del14导致产生一个细长的异常蛋白（p.A52RfsX351），能够转移到细胞核中，但在响应性启动子上完全不活跃。结论：在183例甲状腺功能减退婴儿中，根据blt样表型选择的2例患者中发现了2个新的NKX2-1杂合移码突变。这2名儿童的非典型甲状腺功能减退表型（伴有舌异位的CH或出生后发病的IMH）进一步扩大了与NKX2-1突变相关的临床谱。(C) 2014年欧洲甲状腺协会出版，S. Karger AG，巴塞尔
Objectives: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of postnatal onset. Methods: The candidates were selected by a case-finding approach in 130 CH and 53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex ligation-dependent probe amplification. The variants were studied in vitro, by expression analyses and luciferase bioassay. Results: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were identified. Two children were affected with respiratory distress and CH, but wild-type NKX2-1 gene. The remaining two presented choreic movements and no pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with lingual ectopy and the other one IMH with gland in situ. They were carriers of new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and c.153_166del14). The c. 177delG leads to a prematurely truncated protein (p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to the generation of an elongated aberrant protein (p.A52RfsX351) able to translocate into the nucleus, but completely inactive on a responsive promoter. Conclusions: Two novel heterozygous frameshift mutations of NKX2-1 were identified in 2 cases selected on the basis of a BLT-like phenotype among 183 hypothyroid infants. The atypical hypothyroid phenotypes of these 2 children (CH with lingual ectopy or IMH of postnatal onset) further expand the clinical spectrum that can be associated with NKX2-1 mutations. (C) 2014 European Thyroid Association Published by S. Karger AG, Basel