Novel Inactivating Missense Mutations in the Thyrotropin Receptor Gene in Japanese Children with Resistance to Thyrotropin

Abstract

We describe Japanese siblings with resistance to thyrotropin (TSH) who are compound heterozygotes for two novel mutations in the TSH receptor gene. The affected siblings had increased serum TSH, normal serum thyroid hormones, and normal positioned but slightly hypoplastic thyroid glands. The mutated paternal allele has the substitution of His (CAC) in place of Arg (CGC) at codon 450 (R450H) of the TSH receptor. The mutated maternal allele has the substitution of Ser (AGT) in place of Gly (GGT) at codon 498 (G498S) of the TSH receptor. COS-7 cells transfected with the R450H mutant exhibited a slightly decreased TSH binding and a slightly decreased cyclic adenosine monophosphate (cAMP) response to TSH, whereas cells transfected with the G498S mutant exhibited a markedly decreased TSH binding and a markedly decreased cAMP response to TSH. Flow immunocytofluorometry analysis demonstrated that the G498S mutant resulted in extremely low expression at the cell surface as compared with the wild type receptor and the R450H mutant, in spite of a normal intracellular synthesis. The present cases are the first Japanese patients with TSH resistance in whom mutations in the TSH receptor gene have been identified. These novel mutations may contribute to understanding of the struc-ture-function relationship of the TSH receptor.

Longitudinal Evaluation of Patients with a Homozygous R450H Mutation of the TSH Receptor Gene

“…Both activating and inactivating mutations have been described for the TSHR gene. To date, 33 different loss of function mutations of the TSHR gene have been reported [4,5,6,7,8,9,10,11,12,13,14,15,16,17]. These mutations lead to a wide spectrum of biochemical, clinical, and morphological alterations, depending on the degree of impairment of TSHR function.…”

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

“…After this report，many other mutations were discovered in patients with variable TSH unresponsiveness and different thyroid developmental status [2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In some of these patients [3][4][5][6][7][8][9], TSH resistance was exemplified by normal free thyroid hormones with elevated TSH levels (defined as compensated hypothyroidism or subclinical hypothyroidism) and a normal or hypoplastic thyroid gland. Mild hypothyroidism was seen in four patients [10][11][12] with greatly elevated serum TSH associated with slightly low thyroid hormone levels and normal thyroid gland.…”

“…Up to now, most molecular genetic researches on CH have been done in western countries, some have been carried out in Japanese population [6,28,29]. However,TSHR and TTF-1 genes mutations/variants have not been reported in Chinese population.…”

The Clinical Spectrum of Thyrotropin Receptor Gene (TSHR) Mutations

“…The degree of CH is variable and depends on the genotype. Severe forms manifest as overt CH (Bretones et al, 2001;Gagne et al, 1998;Jeziorowska et al, 2006;Park et al, 2004;Tonacchera et al, 2000), moderate forms as hypothyroidism identified by neonatal screening without clinical symptoms of hypothyroidism (Abramowicz et al, 1997;Jordan et al, 2003), and mild forms present with hyperthyrotropinemia and normal thyroid hormones (de Roux et al, 1996;Nagashima et al, 2001;Narumi et al, 2009;Tenenbaum-Rakover et al, 2009). Gagne et al (1998) described a case of CH with persistent neonatal jaundice, myxedematous facies, large fontanelle and absence of ossification centers of the knee on x-rays, indicating severe prenatal deficiency of thyroid hormone.…”

“…It was only in 1995 that the cause for RTSH syndrome in that case was shown to be a mutation in TSHR (Sunthornthepvarakul et al, 1995). Since the first report of CH caused by a TSHR mutation, several cases of loss-offunction mutations of TSHR have been reported: most are missense mutations, but deletions and insertions have been identified as well (see http: www.hgmd.cf.ac.uk/ac/ gene.php?gene=TSHR and OMIM#275200) (Abramowicz et al, 1997;Alberti et al, 2002;Biebermann et al, 1997Biebermann et al, , 2010Bretones et al, 2001;Camilot et al, 2005;Cangul et al, 2010;Clifton-Bligh et al, 1997;De Marco et al, 2009;de Roux et al, 1996;Fricke-Otto et al, 2005;Gagne et al, 1998;Grasberger et al, 2007;Jeziorowska et al, 2006;Jordan et al, 2003;Kanda et al, 2006;Nagashima et al, 2001;Narumi et al, 2009;Narumi et al, 2011;Park et al, 2004; …”