Carré Aurore, Szinnai Gabor, Castanet Mireille, Sura-Trueba Sylvia, Tron Elodie, Broutin-L'Hermite Isabelle, Barat Pascal, Goizet Cyril, Lacombe Didier, Moutard Marie-Laure, Raybaud Christine, Raynaud-Ravni Catherine, Romana Serge, Ythier Hubert, Léger Juliane, Polak Michel
University Paris-Descartes, INSERM U845, 75270 Paris, France.
Hum Mol Genet. 2009 Jun 15;18(12):2266-76. doi: 10.1093/hmg/ddp162. Epub 2009 Mar 31.
Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13. Functional analysis of the three missense mutations revealed loss of transactivation capacity on the human thyroglobulin enhancer/promoter. Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published patients with NKX2-1 mutations ranged from the complete triad of brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%; recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic interstitial lung disease, and 16% died. In conclusion, we describe five new NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the deficient transactivating capacity in one case. Additionally, our review shows that the majority of affected patients display neurological and/or thyroidal problems and that, although less frequent, lung disease is responsible for a considerable mortality.
甲状腺转录因子1（NKX2-1/TITF1）突变会导致脑-肺-甲状腺综合征，其特征为先天性甲状腺功能减退症（CH）、婴儿呼吸窘迫综合征（IRDS）和良性遗传性舞蹈病（BHC）。本研究的目的是：（i）检测伴有肺部疾病和/或BHC的CH患者中的NKX2-1突变；（ii）对新突变进行体外功能分析；（iii）描述脑-肺-甲状腺综合征的表型谱。我们鉴定出三个新的杂合错义突变（L176V、P202L、Q210P）、一个剪接位点突变（376-2A→G）以及14q13处NKX2-1的一个缺失。对这三个错义突变的功能分析显示，其对人甲状腺球蛋白增强子/启动子的反式激活能力丧失。有趣的是，我们发现共转染PAX8-WT可完全挽救NKX2-1-P202L的转录活性缺陷，而L176V和Q210P则消除了这种协同效应。6例我们自己的以及40例已发表的携带NKX2-1突变患者的临床谱范围包括脑-肺-甲状腺综合征的完整三联征（50%）、脑和甲状腺疾病（30%）以及孤立的BHC（13%）。甲状腺形态正常的占55%，61%出现代偿性甲状腺功能减退。54%的患者发生肺部疾病（足月时IRDS占76%；反复肺部感染占24%）。随访中，20%发展为严重的慢性间质性肺病，16%死亡。总之，我们描述了五个新的NKX2.1突变，其中一例首次发现PAX8可完全挽救其缺陷的反式激活能力。此外，我们的综述表明，大多数受影响患者存在神经和/或甲状腺问题，并且尽管肺部疾病发生频率较低，但却是导致相当比例死亡率的原因。
