title: Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.
abstract: Three genes, TTF1, TTF2, and PAX8, involved in thyroid gland development and migration have been identified. Yet systematic screening for defects in these genes in thyroid dysgenesis gave essentially negative results. In particular, no TTF1 gene defects were found in 76 individuals with thyroid dysgenesis even though a deletion of this gene in the mouse results in thyroid and lung agenesis and defective diencephalon. We report a 6-year-old boy with predominant dyskinesia, neonatal respiratory distress, and mild hyperthyrotropinemia. One allele of his TTF1 gene had a guanidine inserted into codon 86 producing a nonsense protein of 407, rather than 371, amino acids. The mutant TTF1 did not bind to its canonical cis-element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TTF1. Failure of the mutant TTF1 to interfere with binding and transactivation functions of the wild-type TTF1 suggested that the syndrome was caused by haploinsufficiency. This was confirmed in mice heterozygous for Ttf1 gene deletion, heretofore considered to be normal. Compared with wild-type littermates, Ttf1(+/-) mice had poor coordination and a significant elevation of serum thyrotropin. Therefore, haploinsufficiency of the TTF1 gene results in a predominantly neurological phenotype and secondary hyperthyrotropinemia.
authors.affiliation: Children's Hospital of Johannes Gutenberg, University of Mainz, Mainz, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Pohlenz
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dumitrescu
authors.forename: Dorothee
authors.initials: D
authors.lastname: Zundel
authors.forename: Ursula
authors.initials: U
authors.lastname: Martiné
authors.forename: Winfried
authors.initials: W
authors.lastname: Schönberger
authors.forename: Eugene
authors.initials: E
authors.lastname: Koo
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cohen
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002493:Central Nervous System Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002648:Child; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome; D013959:Thyroid Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
chemical_list: C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D004247:DNA