Functional Study of a Novel Single Deletion in theTITF1/NKX2.1Homeobox Gene That Produces Congenital Hypothyroidism and Benign Chorea But Not Pulmonary Distress

Autor: María Bargadá, P. Martul, Guiomar Perez de Nanclares, Christian M. Moya, Pilar Santisteban, Enric Vicens-Calvet, Raquel Coya, J. Ramón Bilbao, Luis Castaño, Neus Potau, Antonio Carrascosa
Rok vydání: 2006
Předmět:
Lung Diseases
Transcriptional Activation
medicine.medical_specialty
Thyroid Nuclear Factor 1
DNA
Complementary
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
DNA Mutational Analysis
Molecular Sequence Data
Clinical Biochemistry
Thyroid Transcription Factor 1
Electrophoretic Mobility Shift Assay
Neuropsychological Tests
Biology
medicine.disease_cause
Biochemistry
Endocrinology
Benign hereditary chorea
Hypothyroidism
Chorea
Internal medicine
Databases
Genetic
medicine
Humans
Pulmonary surfactant-associated protein B
Amino Acid Sequence
Gene
Genetics
Respiratory Distress Syndrome
Newborn
Mutation
Reverse Transcriptase Polymerase Chain Reaction
Biochemistry (medical)
Infant
Newborn
Infant
Nuclear Proteins
Promoter
Mutagenesis
Site-Directed
Female
Thyroglobulin
Psychomotor Performance
Plasmids
Transcription Factors
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1945-7197
0021-972X
DOI: 10.1210/jc.2005-1497
Popis: 10 pages, 8 figures.-- et al.
[Context]: We studied two sisters with congenital hypothyroidism and choreoathetosis but not respiratory distress. [Objective]: The aim of this study was to establish the genetic defect that causes this phenotype and study the molecular mechanisms of the pathology by means of functional analysis. [Design]: Sequencing of DNA, expression vectors generation, EMSAs, transfections experiments as well as bioinformatics analysis were performed. [Results]: We found a new single deletion (825delC) in one allele of the TITF1/NKX2.1 gene. The mutation located in the C-terminal domain generates a nonsense thyroid transcription factor 1 (TTF1) protein, with 22 amino less and rich in positive charges. This protein shows diminished binding to DNA, does not interfere with wild-type (wt) TTF1 binding, and fails to activate reporter genes harboring the thyroglobulin (Tg), thyroperoxidase (TPO), or surfactant protein B (SP-B) promoters. In addition, the mutant (mut) protein has a dominant-negative effect on the transcriptional activity of wt TTF1 in a promoter-specific manner, inhibiting the transcription of Tg and TPO but not of SP-B. Using a Gal4 reporter system, we demonstrate that the mut protein is not transcriptionally active and does not likely compete with the wild type for coactivators. Interestingly, the mut protein impairs the wt capacity to synergize with paired box 8 (PAX8). This cooperation is necessary for Tg and TPO transcription but dispensable for SP-B expression. [Conclusion]: These results are concordant with the phenotype of the two sisters studied and demonstrate a differential role for TTF1 in the different tissues in which it is expressed.
This work was supported by grants from the Dirección General de Investigación BFU2004-03169 (Ministerio Educación y Ciencia), Fondo Investigaciones Sanitarias (FIS) of the Instituto de Salud Carlos III Red Grupos Diabetes Mellitus (C03/212), Red Centro Metabolismo Nutrición (C03/08), and PI041216, Comunidad Autónoma Madrid GR/SAL/0773/2004 and Pfizer (Spain).
Databáze: OpenAIRE
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