Study of Four New Kindreds with Inherited Thyroxine-Binding Globulin Abnormalities POSSIBLE MUTATIONS OF A SINGLE GENE LOCUS

Refetoff, Samuel; Robin, Noel I.; Alper, Chester A.

doi:10.1172/jci106880

Cited by 85 publications

(52 citation statements)

References 45 publications

(118 reference statements)

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“…Subsequently, careful study of a number of families with absent or low TBG have provided evidence for X-linked inheritance (31). In the present work, we were able to identify a clone from an X chromosome library that contains sequences coding for TBG.…”

Section: Discussionmentioning

confidence: 66%

Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases.

Flink¹,

Bailey²,

Gustafson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

162

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Antibodies directed against thyroxine-binding globulin (TBG) have been used to screen a human liver Xgtll expression library. A 1.46-kilobase clone was identified which encodes nearly the complete amino acid sequence, beginning at amino acid 17 of the mature protein. To complete the protein sequence, the cDNA clone was used to identify a genomic clone coding for TBG in a human X chromosome library. The overlapping recombinant clones contained an open reading frame coding for 415 amino acids followed by a polyadenylylation signal (AATAAA) located 275 nucleotides from a TAG termination codon. Beginning at residue 21, the deduced amino acid sequence agrees closely with the known NH2-terminal sequence of the mature peptide. The preceding 20 amino acid residues are hydrophobic in character and presumably represent a leader sequence. Four glycosylation sites were identified, corresponding to the number determined for the purified protein. DNA blot hybridization revealed a single-copy gene, which by chromosomal analysis was found to be located on the long arm of the X chromosome. Unexpectedly, the nucleotide sequence of TBG is closely homologous to those encoding the plasma serine antiproteases a1-antichymotrypsin and a1-antitrypsin. However, there is little overall homology between TBG and transthyretin (prealbumin), the other major thyroxine-binding protein of human plasma.In most vertebrate species, thyroxine-binding globulin (TBG) has been reported to be the major thyroxine-binding protein (1). It is a glycoprotein (molecular mass about 54 kDa) that is synthesized in the liver as a polypeptide of 45 kDa (2). TBG represents a relatively rare translation product of total liver mRNA, accounting for only about 0.018% of total acidprecipitable radioactivity (2). Efforts to obtain detailed information about the structure of TBG and its thyroxinebinding site have been hampered by the presence of multiple electrophoretic forms and the inability to crystallize the protein (3, 4).In this report, we describe the use of serum containing polyclonal antibodies directed against human TBG to isolate cDNA clones coding for TBG from a human liver Xgtll expression library (5). To complete the coding sequence, one of these clones was used to identify a genomic clone from a human X chromosome library. Residues 21-40 of the deduced amino acid sequence correspond closely to the NH2-terminal amino acid sequence of mature TBG reported by Cheng (6). Amino acids 1-20 are very hydrophobic in nature and presumably represent the leader sequence of the propeptide. Unexpectedly, TBG shows a high degree of homology to a1-antichymotrypsin and a1-antitrypsin, and appears to belong to the serpin superfamily, most of which are serine proteinase inhibitors (7,8

show abstract

Section: Discussionmentioning

confidence: 66%

Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases.

Flink¹,

Bailey²,

Gustafson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

162

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“…Thyroid hormone resistance syndrome: These are rare disorders that can be classified as 2 entities: generalized resistance to thyroid hormone and central resistance to thyroid hormone (Refetoff et al, 1993(Refetoff et al, , 1972. Patients with generalized resistance exhibit a reduced peripheral sensitivity to thyroid hormone.…”

Section: Rare: Rare Causes Include Inborn Errors Of Thyroid Hormone Smentioning

confidence: 99%

“…It is a familial condition caused by mutations of the T 3 receptor, which results in a lower affinity for thyroid hormone. Usually, this is a single base mutation, although the patients initially studied by Refetoff et al (1967Refetoff et al ( , 1972 had a larger deletion in the T 3 -receptor beta gene. In both disorders, mutations to the thyroid hormone receptor are localized to the hormone-binding domain.…”

Section: Rare: Rare Causes Include Inborn Errors Of Thyroid Hormone Smentioning

confidence: 99%

Hypothyroidism in adults: A review and recent advances in management

Bello¹

2012

J. Diabetes Endocrinol.

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Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone or, more rarely, from their impaired activity at tissue level. In its clinically overt form, hypothyroidism is a relatively common condition, with an approximate prevalence of 2% in adult women and 0.2% in adult men. Deficiency of the hormone has a wide range of effects, because all metabolically active cells require thyroid hormone. The clinical features of hypothyroidism are dependent on the patient's age, the presence of other disease, and the rate at which hypothyroidism develops. Early detection and proper management is very important. Under treatment leads to disease progression with gradual worsening of symptoms and further metabolic derangements. Fortunately, in most patients older than 3 years, the signs and symptoms of hypothyroidism are reversed with thyroid hormone treatment. A constant reminder on progress in management of the disease is needed. Thus, the aim of this review is to bring to notice the recent advances in the diagnosis and management of hypothyroidism and to highlight the risks involved in the global movement from consuming organic animals (as the world moves towards inorganic foods, which inhibits thyroid hormones).

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“…To our knowledge there have been 29 additional families with high TBG reported since then [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. It is an extremely rare disease even at present in comparison with hereditary TBG deficiency.…”

Section: (Endocrine Journal 41: 467^4701994)mentioning

confidence: 99%

A Family with Hereditary High Serum Thyroxine-Binding Globulln.

et al. 1994

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Abstract. A family with hereditary high serum thyroxine-binding globulin was studied. All the subjects studied were clinically euthyroid without goiter. The propositus (female), her mother and sister had high TBG, total T4 and total T3 with normal free T4, free T3 and TSH. Her father's thyroid function was within the normal range. Possible etiologic factors causing secondary hyper-TBG-nemia were ruled out in all the affected subjects. Isoelectric focusing demonstrated qualitatively normal microheterogeneity, ruling out possible TBG variations caused by liver diseases, estrogen therapy or pregnancy. Although the mechanism involved in the TBG increase awaits further investigation, it could be an abnormality in the gene controlling the synthesis of TBG.

show abstract

Study of Four New Kindreds with Inherited Thyroxine-Binding Globulin Abnormalities POSSIBLE MUTATIONS OF A SINGLE GENE LOCUS

Cited by 85 publications

References 45 publications

Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases.

Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases.

Hypothyroidism in adults: A review and recent advances in management

A Family with Hereditary High Serum Thyroxine-Binding Globulln.

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