Functional Study of a Novel Single Deletion in the<i>TITF1/NKX2.1</i>Homeobox Gene That Produces Congenital Hypothyroidism and Benign Chorea But Not Pulmonary Distress

Moya, Christian M.; Nanclares, Guiomar Perez de; Castaño, Luís; Potau, Neus; Bilbao, José Ramón; Carrascosa, Antonio; Bargadá, María; Coya, Raquel; Martul, P.; Vicens-Calvet, E; Santisteban, Pilar

doi:10.1210/jc.2005-1497

Cited by 74 publications

(58 citation statements)

References 64 publications

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“…(Table 1) [12,13,[19][20][21][22]24], indicating that BHC and Brain-Thyroid-Lung syndrome are not entirely distinct but represent extreme points on a spectrum [28]. Intrafamilial phenotypic variation in this disorder may be explained by differences in modifier genes that produce a different genetic background in the same family.…”

Section: Discussionmentioning

confidence: 99%

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

Nakamura¹,

Sekijima²,

Nagamatsu³

et al. 2012

Journal of the Neurological Sciences

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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

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Section: Discussionmentioning

confidence: 99%

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

Nakamura¹,

Sekijima²,

Nagamatsu³

et al. 2012

Journal of the Neurological Sciences

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“…In 1998, Devriendt et al [21] firstly described a neonate with respiratory failure, mild primary hypothyroidism, and neurological dysfunction (including developmental delay, hypotonia, and truncal ataxia), caused by a heterozygous deletion of chromosome 14q13-21. Since then, several patients with chromosomal deletions [22] and point mutations in this gene [23][24][25][26][27] have been found, which had a complex phenotype that included thyroid, respiratory, and neurological defects. These findings suggested that mutations in TTF-1 gene might result in a complex disease affecting thyroid, lungs, and brain.…”

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confidence: 99%

Thyrotropin Receptor and Thyroid Transcription Factor-1 Genes Variant in Chinese Children with Congenital Hypothyroidism

et al. 2008

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Abstract. The aim of the present study was to investigate the mutation/variant of thyrotropin receptor (TSHR) and thyroid transcription factor-1 (TTF-1) genes in Chinese children with congenital hypothyroidism (CH). Seventy-nine and forty-nine Chinese children with CH were enrolled for molecular analysis of the TSHR gene and TTF-1 gene, respectively. One hundred normal children were evaluated as control. The coding regions of TSHR and TTF-1 genes were amplified by polymerase chain reaction and sequenced. Sequencing of the TSHR gene revealed a compound heterozygous variants (Pro52Thr/Val689Gly) and a heterozygous variant (Gly245Ser) in 2 of 79 patients. In 30 patients and 33 controls the normal cytosine at position 2181 in exon 10 of TSHR gene was replaced by a guanine， resulting in the replacement of Asp 727 by Glu. In 47 patients and 50 controls, the normal thymidine at position 561 in exon 7 of TSHR gene was replaced by a cytosine. This substitution did not change the amino acid in position 187. Sequencing of the TTF-1 gene revealed no mutation or polymorphism in 49 patients and 100 controls. In conclusion, three heterozygous variants (Pro52Thr, Gly245Ser, Val689Gly) of TSHR gene were firstly detected in Chinese children with CH. There were polymorphisms in exon 10 at nucleotide 2181 (C/G) and in exon 7 at nucleotide 561 (T/C) in TSHR gene. No mutation or polymorphism was detected in the coding region of TTF-1 gene. The mutation/variant of TSHR and TTF-1 genes is relatively rare in Chinese children with CH.

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“…To the best of our knowledge, the patients with TITF1 mutations or deletions that described thyroid phenotypes have been identified in 14 sporadic or familial cases [6][7][8][9][10][11][12][13][14][15] (Table 1). Although thyroid function studies remain poor, most patients have mild (compensated) hypothyroidism with elevated TSH levels and normal or hypoplastic thyroid glands.…”

Section: Discussionmentioning

confidence: 99%

Mutation of a Gene for Thyroid Transcription Factor-1 (TITF1) in a Patient with Clinical Features of Resistance to Thyrotropin

et al. 2008

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Abstract. Resistance to TSH (RTSH [MIM 275200]) is a heterogeneous condition defined by variable degree of insensitivity to biologically active TSH. While this condition is classically caused by loss-of-function mutations of the TSH receptor gene (TSHR), several patients have exhibited RTSH-like phenotype in the apparent absence of TSHR mutations, and some of them have mutations of PAX8 or GNAS1. We identified a Japanese boy with congenital hypothyroidism who suffered from recurrent lower respiratory infection during infancy and choreoathetosis at a later age. At 14 years of age, he was diagnosed as having RTSH, on the basis of compensated hypothyroidism (TSH, 30.2 mU/L; FT4, 1.2 ng/dl), disproportionate increments of thyroid hormones and TSH during a TRH test (ΔFT3, 0.4 pg/ml; ΔT3, 13 ng/dl; and ΔTSH, 88.3 mU/L), and normal ultrasound thyroid image and radioactive iodine uptakes. Molecular analysis for TITF1 revealed a novel de novo heterozygous deletion/insertion mutation (c.470_479delinsGCG,) that is predicted to lose the entire homeodomain and the NK2-specific domain. We suggest that a heterozygous loss-of-function TITF1 mutation can also cause RTSH-compatible phenotype.

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

Abstract: 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.

Cited by 74 publications

References 64 publications

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

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

Thyrotropin Receptor and Thyroid Transcription Factor-1 Genes Variant in Chinese Children with Congenital Hypothyroidism

Mutation of a Gene for Thyroid Transcription Factor-1 (TITF1) in a Patient with Clinical Features of Resistance to Thyrotropin

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