Identification of TSH receptor mutations in three families with resistance to TSH

Tonacchera, Massimo; Cosmo, Caterina Di; Marco, Giuseppina De; Agretti, Patrizia; Banco, Mariaelena; Perri, Anna; Gianetti, Elena; Montanelli, Lucia; Vitti, Paolo; Pinchera, Aldo

doi:10.1111/j.1365-2265.2007.02950.x

Cited by 29 publications

(13 citation statements)

References 26 publications

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“…The recent finding that TSHR, like other G protein-coupled receptors, can oligomerize in living cells led to the hypothesis that the formation of complexes between wildtype and mutant receptors may be responsible for partial TSH resistance in patients with heterozygous TSH-R mutations (34). In our series of subjects, we detected eight known nonsynonymous mutations in the heterozygous state, which was previously demonstrated to lead to a loss of function of the THS-R (11)(12)(13)35). The P27T variant, found in only one child, was not reported to play a functional role and was considered a polymorphism (35).…”

Section: Genetic Factorsmentioning

confidence: 80%

Subclinical Hypothyroidism in Children and Adolescents: A Wide Range of Clinical, Biochemical, and Genetic Factors Involved

Rapa

Monzani

Moia

et al. 2009

The Journal of Clinical Endocrinology & Metabolism

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Section: Genetic Factorsmentioning

confidence: 80%

Subclinical Hypothyroidism in Children and Adolescents: A Wide Range of Clinical, Biochemical, and Genetic Factors Involved

Rapa

Monzani

Moia

et al. 2009

The Journal of Clinical Endocrinology & Metabolism

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“…Even though there are no hotspots in the gene sequence of this receptor, this exon was chosen because it contains the majority of the CH-provoking mutations described in the literature 6,7,15,16 .…”

Section: Discussionmentioning

confidence: 99%

High Frequency of D727E Polymorphisms in Exon 10 of the TSHR Gene in Brazilian Patients with Congenital Hypothyroidism

Alves

Cruz

Pimentel

et al. 2010

Journal of Pediatric Endocrinology and Metabolism

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Congenital Hypothyroidism affects between 1:3000 and 1:4000 newborn infants in iodinesufficient regions. Some studies have shown that mutations and polymorphisms in the TSH receptor gene are responsible for this disease. In the present study, mutations of exon 10 of the TSH receptor gene were investigated in Congenital Hypothyroidism patients. In the present study a sample of 90 Brazilian patients with primary congenital hypothyroidism was analyzed. Genomic DNA was isolated from peripheric blood samples. Exon 10 of the TSH receptor gene was amplified by PCR, and amplicons were automatically sequenced. Three nucleotide alterations were identified: c.1377G>A (A459A), c.1935G>A (L645L), and c.2181C>G (D727E). A459A polymorphism was also described previously in patients with thyroid cancer. The nucleotide alteration L645L was found in a single patient. This is the first time the L645L mutation has been described. D727E polymorphism showed high frequency (allele frequency 10%) in present study when compared to others reports.

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“…Loss-of-function in TSHR causes TSH resistance due to variably reduced sensitivity to TSH. Since 1995, 33 different loss-of-function mutations of the TSHR gene have been reported (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). It has been shown that TSHR gene mutations can cause a wide spectrum of thyroid abnormalities, ranging from severe hypoplasia to an almost normal sized and structured thyroid gland (24,25).…”

Section: Introductionmentioning

confidence: 98%

Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese

Kanda

Mizuno

Sugiyama

et al. 2006

Endocr

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Loss-of-function mutations in the thyrotropin receptor (TSHR) gene were described as a syndrome characterized by thyroid hyposensivity to biologically active TSH, ranging from euthyroid to severe hypothyroidism. In Japanese, a common mutation in the TSHR gene is R450H, which demonstrated moderately impaired receptor function. We studied six subjects of Japanese origin whose major abnormality was persistent hyperthyrotropinemia by genetic sequence analysis of the TSHR gene. Three subjects were homozygous for the R450H mutation, whereas the three remaining subjects were single heterozygous. Homozygous subjects displayed mild hypothyroidism confirmed by moderately elevated basal TSH levels and excessive TSH response to TRH administration. Heterozygous subjects also demonstrated fully or partially compensated hypothyroidism, but less severe than that of homozygous subjects. More frequent involvement of the R450H mutation in the TSHR gene in Japanese was identified. In addition, a good correlation between phenotype and genotype was demonstrated in respect to biochemical analysis and drug dosage. Our observations showed clinical significance of heterozygosity associated with compensated hypothyroidism in spite of only mildly impaired receptor function.

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Identification of TSH receptor mutations in three families with resistance to TSH

Abstract: We identified TSH receptor mutations in seven members of three families with subclinical hypothyroidism.

Cited by 29 publications

References 26 publications

Subclinical Hypothyroidism in Children and Adolescents: A Wide Range of Clinical, Biochemical, and Genetic Factors Involved

Subclinical Hypothyroidism in Children and Adolescents: A Wide Range of Clinical, Biochemical, and Genetic Factors Involved

High Frequency of D727E Polymorphisms in Exon 10 of the TSHR Gene in Brazilian Patients with Congenital Hypothyroidism

Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese

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