title: Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea.
abstract: Benign hereditary chorea (BHC) is an autosomal dominant disorder of early onset characterised by non progressive choreic movements with normal cognitive function occasionally associated with hypothyroidism and respiratory problems. Numerous pieces of evidence link BHC with TITF-1/NKX2.1 gene mutations. We studied a patient with a familial benign hereditary chorea and normal thyroid and respiratory function. Sequence analysis of TITF-1 revealed the presence of a heterozygous C>T substitution at nucleotide 532, predicted to change an arginine (CGA) with a stop codon (TGA) at position 178 (R178X). A functional analysis shows that the mutated TTF-1 is not binding DNA, nor activating the canonical thyroid target gene promoter or interfering with the ability of wild type TTF-1 to activate transcription. In addition, the mutated protein is predominantly cytoplasmic, rather than nuclear as in the case of the wild type TTF-1. Thus, we have identified a new mutation in the TTF-1 coding gene in a patient with benign hereditary chorea. The results show that the mutation leads to a haploinsufficiency of TITF-1 and opens the question of genotype/phenotype correlation.
authors.affiliation: Institute of Neurobiology and Molecular Medicine, National Council Research, Via Fosso del Cavaliere 100, 00133 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Provenzano
authors.forename: Liana
authors.initials: L
authors.lastname: Veneziano
authors.forename: Richard
authors.initials: R
authors.lastname: Appleton
authors.forename: Marina
authors.initials: M
authors.lastname: Frontali
authors.forename: Donato
authors.initials: D
authors.lastname: Civitareale
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics; D002819:Chorea / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D018389:Codon, Nonsense / Q000235:genetics; D003593:Cytoplasm / Q000235:genetics; D004252:DNA Mutational Analysis; D004739:England; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D051381:Rats; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D005819:Genetic Markers; C000614412:NKX2-1 protein, human; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors