Genetics and phenomics of hypothyroidism due to TSH resistance

Persani, Luca; Calebiro, Davide; Cordella, Daniela; Weber, Giovanna; Gelmini, Giulia; Libri, Domenico; Filippis, Tiziana de; Bonomi, Marco

doi:10.1016/j.mce.2010.01.008

Cited by 100 publications

(83 citation statements)

References 107 publications

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“…Moreover, the carriers of CH and WD usually show subclinical disease manifestations related to decreased enzyme activity. 33 Therefore, we highly recommend molecular genetic prenatal screening of Korean individuals to identify relevant mutations. In addition, it is important to screen for carriers in the Korean population to identify couples that are heterozygous for fatal genetic diseases, in order to reduce the incidence of these diseases and prevent homozygosity for these disorders.…”

Section: Discussionmentioning

confidence: 99%

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Song

Lee

et al. 2011

J Hum Genet

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Although many studies have been performed to identify mutations in Korean patients with various autosomal-recessive Mendelian disorders (AR-MDs), little is known about the carrier frequencies of AR-MDs in the Korean population. Twenty common mutations from six AR-MDs, including Wilson disease (WD), non-syndromic hearing loss (NSHL), glycogen storage disease type Ia (GSD Ia), phenylketonuria (PKU), congenital hypothyroidism (CH), and congenital lipoid adrenal hyperplasia (CLAH) were selected to screen for based on previous studies. A total of 3057 Koreans were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry followed by confirmation using the Sanger sequencing. We found 201 and 8 carriers with either one or two mutations in different genes, respectively, yielding a total carrier frequency of 1 in 15 (6.7%). Of the six AR-MDs, NSHL has the highest carrier frequency followed by WD, CH, CLAH, GSD Ia, and PKU. As carrier screening tests are becoming prevalent and the number of mutations known and tested is rising, a priori data on the carrier frequencies in different ethnic groups is mandatory to plan a population screening program and to estimate its efficiency. In light of this, the present results can be used as a basis to establish a screening policy for common AR-MRs in the Korean population.

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Section: Discussionmentioning

confidence: 99%

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Song

Lee

et al. 2011

J Hum Genet

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“…TSHR mutations result in wide spectrum of clinical manifestations ranging from mild to severe hypothyroidism and hyperthyroidism (63). Up to this date more than 40 kinds of loss of function mutations in the TSHR gene have been reported as the causative defect in congenital hypothyroidism (64). By contrast, gain of function mutations in the TSHR gene were identified in familial non-autoimmune hyperthyroidism or sporadic non-autoimmune hyperthyroidism (65).…”

Section: Clinical Manifestation Of Th Signaling Related Mutations In mentioning

confidence: 99%

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Kim

Mohan

2013

Bone Res.

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The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor (TR) α and β, of which TRα seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance. Keywords: thyroid hormone; bone; cartilage; growth factors; bone cells Bone Research (2013) 2: 146-161. doi: 10.4248/BR201302004 IntroductionThyroid hormone (TH) plays an important role in normal endochondral ossification and is essential for skeletal development, linear growth, maintenance of bone mass, and efficient fracture healing ( 1). Juvenile hypothyroidism causes growth arrest with delayed bone formation and mineralization, and T4 replacement induces rapid catch-up growth (2). By contrast, childhood thyrotoxicosis accelerates bone formation with premature closure of the growth plates and skull sutures, leading to short stature and craniosynostosis (3). Although there is considerable evidence regarding the importance of TH in skeletal development, the molecular mechanisms of TH action in bone are poorly understood. In this chapter, we discuss regulation and mechanisms of action of TH during skeletal development with particular emphasis on areas in which recent advances have been made. Physiology of TH: Regulation, metabolism and TH receptorRegulation Systemic TH levels are maintained by the classical negative feedback loop involving the hypothalamus-pituitary--thyroid (HPT) axis ( Figure 1). Thyrotropin releasing hormone (TRH) is synthesized in the paraventricular nucleus (PVN) of the hypothalamus and stimulates synthesis and secretion of thyroid stimulating hormone (TSH) fromHa-Young Kim et al. www.boneresearch.org | Bone Research 147thyrotroph cells in the anterior pituitary gland. TSH subsequently acts via the TSH receptor (TSHR) on thyroid follicular cells to stimulate synthesis and release of 3,5...

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“…The degree of TSH resistance depends on the severity of the impairment of the receptor function caused by the mutation and on the number of mutated alleles (30). In cases of both alleles carrying mutant receptors with complete lack of function, the typical result is severe congenital hypothyroidism with a hypoplastic thyroid gland (uncompensated TSH resistance).…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterization of a novel thyrotropin receptor mutation (V87L) in a Chinese woman with subclinical hypothyroidism

Zhang

Zhou

Dong

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The thyrotropin receptor (TSHR) gene has been defined as a highly mutable gene. Mutations in the TSHR gene result in either gain or loss of the receptor function. Subclinical hypothyroidism (SH) is a clinical condition defined as an elevated serum TSH level associated with normal free thyroxine and free triiodothyronine. Chronic autoimmune thyroiditis is the most frequent cause of subclinical hypothyroidism in adults. In rare cases, a loss-of-function mutation of TSHR is the cause of SH. In the present study, a novel TSHR mutation (V87L; confirmed to be a loss-of-function mutation) was identified in a 59-year-old Chinese woman, as the potential cause of the patient's subclinical hypothyroidism. The case may provide valuable insight into the etiology of SH.

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Genetics and phenomics of hypothyroidism due to TSH resistance

Cited by 100 publications

References 107 publications

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

Identification and functional characterization of a novel thyrotropin receptor mutation (V87L) in a Chinese woman with subclinical hypothyroidism

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