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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

1
Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics, La Paz University Hospital, Madrid, Spain.
2
Biomedical Research Institute "Alberto Sols," Spanish National Council for Scientific Research-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
3
Centro de Investigación Biomédica en Red Cáncer from Health Institute Carlos III (CIBERONC), Madrid, Spain.
4
Department of Paediatric Endocrinology, 12 de Octubre University Hospital, Madrid, Spain.
5
Department of Paediatric Pneumology and Allergy, 12 de Octubre University Hospital, Madrid, Spain.
6
Department of Neuropaediatry, 12 de Octubre University Hospital, Madrid, Spain.
7
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Abstract

Context:

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.

Objective:

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

Methods:

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.

Results:

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.

Conclusions:

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.

PMID:
29294041
DOI:
10.1210/jc.2017-01241
[Indexed for MEDLINE]

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