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

Abstract

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.BHC with a novel TITF-1 mutation 3

Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum

“…Thyroid transcription factor 1 protein also plays an important role in thyroid and lung organogenesis . Previous reviews have suggested that approximately half of all individuals with NKX2.1 mutations have the full triad of brain, lung, and thyroid involvement . However, in our series only three out of 10 individuals had involvement of all three organs, despite comprehensive investigation.…”

“…Linkage analysis and positional cloning have identified NKX2.1 as the causative gene, located on chromosome 14q13 (also known as TITF1 , TTF‐1 , TEBP , and NKX2A) . More than 30 different mutations of this gene have been identified to date including whole‐gene deletions as well as splice‐site, frameshift, nonsense, and missense mutations …”

Recurrent drop attacks in early childhood as presenting symptom of benign hereditary chorea caused by TITF1 gene mutations

“…Despite the severe impact on the TITF1 protein, which is usually caused by loss of function mutations, the observed clinical manifestations are variable. Other reported patients with loss of function mutations exhibited a phenotype ranging from BHC to the more severe brain‐thyroid‐lung syndrome, with variable severity even in the same family . More than 90 TITF1 mutations have been reported to date, but attempts to make genotype‐phenotype correlations have remained unsuccessful.…”

Study on DEHAL1 Mutations in Patients with Congenital Hypothyroidism and Thyroid Goiter

“…Congenital hypothyroidism can be divided into two major types according to its pathogenesis. 80%-85% of CH is caused by defective thyroid glands, such as athyreosis, hypoplastic or ectopic gland [4] ,which is closely related to the gene encoding thyroid transcription factor, such as TSHR [5] , TTF1 [6] ,PAX8 [7] ,NKX2.1 [8] and FOXE1 [9] and so on. 15%-20% of CH patients with thyroid dyshormonogenesis combined with thyroid goiter [1] is inherited as an autosomal recessive trait [10] .…”