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

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


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Athetosis / genetics*
  • Chorea / genetics*
  • Congenital Hypothyroidism / genetics*
  • DNA Mutational Analysis / methods
  • Follow-Up Studies
  • Frameshift Mutation*
  • Humans
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Pulmonary Emphysema / congenital
  • Pulmonary Emphysema / genetics
  • Respiratory Distress Syndrome, Newborn / genetics*
  • Thyroid Nuclear Factor 1 / genetics*
  • Trans-Activators
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • Intracellular Signaling Peptides and Proteins
  • NKX2-1 protein, human
  • Thyroid Nuclear Factor 1
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • TAFAZZIN protein, human

Supplementary concepts

  • Choreoathetosis, Hypothyroidism, And Neonatal Respiratory Distress