TAZ/WWTR1 mediates the pulmonary effects of NKX2-1 mutations in Brain-Lung-Thyroid syndrome.

Related Articles

TAZ/WWTR1 mediates the pulmonary effects of NKX2-1 mutations in Brain-Lung-Thyroid syndrome.

J Clin Endocrinol Metab. 2017 Dec 26;:

Authors: Moya CM, Zaballos MA, Garzón L, Luna C, Simón R, Yaffe MB, Gallego E, Santisteban P, Moreno JC

Abstract
Context: Identification of a novel 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 to 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, co-immunoprecipitation 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 BLTS patients 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. Co-expression of the coactivator TAZ/WWTR1 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.
Conclusion: Our study supports 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 [PubMed - as supplied by publisher]

http://ift.tt/2lM9akK