A novel nonsense mutation in the TITF-1 gene in a Japanese family with benign hereditary chorea

A Japanese family with a novel nonsense mutation in the TITF-1 gene (p.Y98X) is described. The proband showed severe generalized chorea, delayed motor development, subnormal intelligence, congenital hypothyroidism, bronchial asthma, and a history of pulmonary infection, all of which are characteristic features of Brain-Thyroid-Lung syndrome. On the other hand, her brother and mother showed a mild benign hereditary chorea (BHC) phenotype with congenital hypothyroidism. Intrafamilial phenotypic variation is common in BHC/Brain-Thyroid-Lung syndrome and suggests the existence of other genetic or environmental factors regulating TITF-1 function. Although choreic movement in BHC/Brain-Thyroid-Lung syndrome is recognized as non-progressive, the proband showed re-exacerbation of choreic movement at puberty. The dopamine agonist, ropinirole hydrochloride, reduced her choreic movements, suggesting that levodopa and/or dopamine agonists may compensate for underdeveloped dopaminergic pathways in this disorder.ArticleJOURNAL OF THE NEUROLOGICAL SCIENCES. 313(1-2):189-192 (2012)journal articl

Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression

The C-terminal activation domain (C-TAD) of the hypoxia-inducible transcription factors HIF-1α and HIF-2α binds the CH1 domains of the related transcriptional coactivators CREB-binding protein (CBP) and p300, an oxygen-regulated interaction thought to be highly essential for hypoxia-responsive transcription. The role of the CH1 domain in vivo is unknown, however. We created mutant mice bearing deletions in the CH1 domains (ΔCH1) of CBP and p300 that abrogate their interactions with the C-TAD, revealing that the CH1 domains of CBP and p300 are genetically non-redundant and indispensable for C-TAD transactivation function. Surprisingly, the CH1 domain was only required for an average of ∼35–50% of global HIF-1-responsive gene expression, whereas another HIF transactivation mechanism that is sensitive to the histone deacetylase inhibitor trichostatin A (TSA(S)) accounts for ∼70%. Both pathways are required for greater than 90% of the response for some target genes. Our findings suggest that a novel functional interaction between the protein acetylases CBP and p300, and deacetylases, is essential for nearly all HIF-responsive transcription