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J Clin Endocrinol Metab. 2018 Mar 1;103(3):839-852. doi: 10.1210/jc.2017-01241.

TAZ/WWTR1 Mediates the Pulmonary Effects of NKX2-1 Mutations in Brain-Lung-Thyroid Syndrome.

Author information

Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics, La Paz University Hospital, Madrid, Spain.
Biomedical Research Institute "Alberto Sols," Spanish National Council for Scientific Research-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
Centro de Investigación Biomédica en Red Cáncer from Health Institute Carlos III (CIBERONC), Madrid, Spain.
Department of Paediatric Endocrinology, 12 de Octubre University Hospital, Madrid, Spain.
Department of Paediatric Pneumology and Allergy, 12 de Octubre University Hospital, Madrid, Spain.
Department of Neuropaediatry, 12 de Octubre University Hospital, Madrid, Spain.
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.



Identification of a frameshift heterozygous mutation in the transcription factor NKX2-1 in a patient with brain-lung-thyroid syndrome (BLTS) and life-threatening lung emphysema.


To study the genetic defect that causes this complex phenotype and dissect the molecular mechanism underlying this syndrome through functional analysis.


Mutational study by DNA sequencing, generation of expression vectors, site-directed mutagenesis, protein-DNA-binding assays, luciferase reporter gene assays, confocal microscopy, coimmunoprecipitation, and bioinformatics analysis.


We identified a mutation [p.(Val75Glyfs*334)] in the amino-terminal domain of the NKX2-1 gene, which was functionally compared with a previously identified mutation [p.(Ala276Argfs*75)] in the carboxy-terminal domain in other patients with BLTS but without signs of respiratory distress. Both mutations showed similar protein expression profiles, subcellular localization, and deleterious effects on thyroid-, brain-, and lung-specific promoter activity. Coexpression of the coactivator TAZ/WWTR1 (transcriptional coactivator with PDZ-binding motif/WW domain-containing transcription regulator protein 1) restored the transactivation properties of p.(Ala276Argfs*75) but not p.(Val75Glyfs*334) NKX2-1 on a lung-specific promoter, although both NKX2-1 mutants could interact equally with TAZ/WWTR1. The retention of residual transcriptional activity in the carboxy-terminal mutant, which was absent in the amino-terminal mutant, allowed the functional rescue by TAZ/WWTR1.


Our results support a mechanistic model involving TAZ/WWTR1 in the development of human congenital emphysema, suggesting that this protein could be a transcriptional modifier of the lung phenotype in BLTS.

[Indexed for MEDLINE]

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