Search PubMed⌕ Search

Biomedical subjects

S Refetoff

Publications and source records attributed to S Refetoff.

At least 37 records · Page 2Linked to original sources
PubMed1995

Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder.

Previous studies have demonstrated an association between resistance to thyroid hormone (RTH) and attention-deficit hyperactivity disorder (ADHD). To determine if the neurocognitive characteristics in individuals with RTH are similar to those observed in ADHD, 12 children with RTH from 7 families were matched to 12 children with ADHD without RTH. Subjects were administered standardized intellectual, developmental, and school achievement tests. Parent and teacher ratings of children's hyperactivity and attention were similar for both groups, as were measures of attention, impulsivity, and verbal IQ. Children with RTH displayed lower nonverbal intelligence (performance IQ = 85) and academic achievement (> 1-2 SD below the mean) when compared with those with ADHD only (performance IQ = 99; achievement within 2 SD). Although children with RTH have behavioral characteristics similar to those with ADHD, their significantly weaker abilities of perceptual-organization and lower school achievement suggest a more severe neurobehavioral impairment than ADHD.

Adolescent↗
PubMed1994

Expression of a thyroid hormone-responsive recombinant gene introduced into adult mice livers by replication-defective adenovirus can be regulated by endogenous thyroid hormone receptor.

We constructed a recombinant adenovirus carrying the firefly luciferase gene driven by the thymidine kinase promoter and controlled by the palindromic thyroid hormone/retinoic acid-responsive element. The same adenovirus vector without the hormone-responsive element was used as control. Regulation of the luciferase gene expression was tested in pituitary-derived GH cells and hepatoma-derived HepG2 cells infected with the recombinant adenoviruses. Administration of triiodothyronine to GH cells and all-trans-retinoic acid to HepG2 cells resulted in 8.0 +/- 0.3-fold and 4.6 +/- 0.5-fold induction of luciferase activity, respectively. No significant increase was observed with the control adenovirus. Hormonal regulation was also examined in adult mice. Mice depleted of thyroid hormone were injected intravenously with the recombinant adenoviruses and given 4 times the replacement dose of triiodothyronine or vehicle only for 4 days. Hormone administration resulted in 4.2-fold increase of luciferase activity in liver homogenates. No significant effect was observed in animals injected with the control adenovirus. This recombinant adenovirus provides a new experimental system in the study of thyroid hormone and retinoic acid action and offers the potential to regulate by physiological means the expression of genes transferred for the purpose of therapy.

Adenoviridae↗
PubMed1994

An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common form of inherited increase of serum thyroxine in Caucasians. It is the result of increased thyroxine-binding to serum proteins and is inherited as a dominant trait. The entire coding region of the albumin gene of a subject with FDH was sequenced. A single nucleotide substitution, G to A transition in codon 218, was found in one of the two alleles, resulting in the replacement of the normal Arg with His. This mutation was found in 9 affected family members but not in 8 unaffected relatives and 18 unrelated normal individuals. The same missense mutation was found in 12 other subjects with FDH belonging to 7 unrelated families. In every individual with FDH, the mutation was associated with the Sac I+ polymorphism in the albumin gene, strongly suggesting a founder effect.

Arginine↗
PubMed1994

Polymorphism of a variant human thyrotropin receptor (hTSHR) gene.

Sequencing of the human thyrotropin receptor (hTSHR) gene using genomic DNA from peripheral blood leukocytes revealed a substitution of nucleotide 253 in the cDNA sequence. The replacement of the wild-type cytosine-253 to adenine results in the replacement of the wild-type Pro at codon 52 (CCC) with Thr (ACC) located in exon 1 of the TSHR. We screened genomic DNAs from 60 unrelated individuals for the presence of A253 by PCR amplification using a degenerate oligonucleotide primer that produces a Tth111 I restriction site only in the presence of A253. We found 12% having heterozygosity and all had normal free thyroxine index (FT4I) and TSH levels. We have no information concerning the functional significance of this amino acid substitution. However, in the heterozygous state, the variant allele does not result in thyroid function abnormalities.

Base Sequence↗
PubMed1994

Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor beta gene resulting in the replacement of the normal proline 453 with serine.

Resistance to thyroid hormone (RTH) is a condition of impaired tissue responsiveness to thyroid hormone characterized by elevated free thyroid hormone levels in serum accompanied by nonsuppressed TSH. RTH has been associated with mutations in the thyroid hormone receptor (TR) beta gene. We report studies carried out in 9 members of a family (F94) of Jewish ethnic origin and a single subject of Mexican origin. All subjects fulfilling the criteria of RTH (6 of family F94 and one of family F27) had the same point mutation in the T3-binding domain on one of the two alleles of the TR beta gene. This mutation resulted in the replacement of the normal proline-453 with serine (P453S). Nevertheless, the clinical characteristics of affected members of each of the two families differed as did the severity of hormonal resistance in terms of responses to the administration of L-T3. Genetic studies indicate that the same mutation occurred independently in each of the two families.

Adult↗
PubMed1994

Resistance to thyroid hormone: an historical overview.

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced tissue responsiveness to thyroid hormone. Subjects have elevated serum thyroid hormone levels in association with a nonsuppressed TSH. Goiter and thyroid test abnormalities have most often led to further investigation, underscoring the paucity of specific clinical manifestations of RTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when dealing with attention deficit or hyperactivity. Failure to recognize the inappropriate persistence of TSH secretion, in spite of elevated thyroid hormone levels, has commonly resulted in erroneous diagnosis leading to treatment aimed to normalize the thyroid hormone level. More than 400 subjects with this syndrome have been identified. The mode of inheritance appears to be autosomal dominant in the majority of families. It has long been suspected that RTH is most likely caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha and TR beta, located in chromosomes 17 and 3, respectively. TR beta gene mutations have been recently identified in 68 families with RTH. All mutations are located in the T3-binding domain, straddling the putative TR-dimerization region. Mutant TRs exhibit hormone-binding impairment, the degree of which does not correlate with the severity of clinical manifestations. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected, while those with point mutations are, indicated that interactions of the mutant TRs with normal TRs and with other factors, are responsible for the dominant inheritance of RTH and its clinical heterogeneity.(ABSTRACT TRUNCATED AT 250 WORDS)

History, 20th Century↗
PubMed1994

Gene screening in Japanese families with complete deficiency of thyroxine-binding globulin demonstrates that a nucleotide deletion at codon 352 may be a race specific mutation.

OBJECTIVE: Thyroxine-binding globulin (TBG) is a serum protein that transports 75% of circulating thyroxine. Eleven naturally occurring mutations in the human TBG gene have been identified, ten of which alter the properties of the molecule. Three of these mutations produce complete deficiency of TBG (TBG-CD) and four are associated with a second mutation in codon 283 (TBG-poly) which is polymorphic in some ethnic groups but, when present alone, does not alter the properties of the TBG molecule. In this communication we investigate whether two unrelated Japanese families with TBG-CD harboured the TBG-CDJ mutation in codon 352 associated with TBG-CD in families residing in more distant locations of the Japanese Islands. In addition we examined the possible association with TBG-poly and its incidence in the Japanese population. DESIGN: Mutant alleles were identified by amplification of genomic DNAs by the polymerase chain reaction, using allele-specific oligonucleotide primers. PATIENTS: Eight family members and 25 normal subjects. MEASUREMENTS: Serum free thyroxine and TBG concentration were measured by a conventional radioimmunoassay and a more sensitive enzyme immunoassay. Genomic DNAs were extracted from white blood cells and specific mutations at codons 352 and 283 were identified by allele-specific amplification. RESULTS: Three males and three females, whose serum TBG levels were decreased, had mutations at codon 352 as hemizygous and heterozygous, respectively. This mutation was not present in the DNA of any of the related or unrelated subjects with normal TBG concentration. The presence of TBG-poly was demonstrated in only one heterozygous family member and in six out of 30 alleles (20%) in normal unrelated subjects. The frequency of this TBG polymorphism in the Japanese is similar to that of 16% reported in French Canadians. CONCLUSIONS: We conclude that TBG-CDJ might be a prevalent cause of complete deficiency of thyroxine-binding globulin in the Japanese and that TBG-poly probably appeared before the divergence of human races.

Alleles↗
PubMed1994

Resistance to thyroid hormone and its molecular basis.

Generalized resistance to thyroid hormone (GRTH) is an inherited syndrome characterized by hyposensitivity of target tissues to thyroid hormone. The clinical presentation is variable. The syndrome is usually suspected when elevated serum thyroid hormone levels are associated with a non-suppressed thyroid-stimulating hormone (TSH). While goiter and thyroid test abnormalities have more often led to the suspicion of thyroid gland dysfunction, short stature, hyperactivity, learning disability and goiter in children or adolescents and recalcitrant goiter in adults, should raise the suspicion of GRTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when confronted with attention deficit, hyperactivity or tachycardia. Failure to recognize the inappropriate persistence of TSH secretion in spite of elevated thyroid hormone levels has commonly resulted in erroneous diagnosis leading to antithyroid treatment. More than 300 subjects with this syndrome have been identified. The mode of inheritance in the majority of families is autosomal dominant. Recessive transmission has been found in only one family. It has long been speculated that this defect is likely to be caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha and TR beta. Mutations in the TR beta gene have been identified in 42 families with GRTH. All are located in the T3-binding domain straddling the putative dimerization region and exhibit various degrees of hormone-binding impairment. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected while those with point mutations are, indicates that interactions of a mutant TR with normal TR and with other factors are responsible for the dominant inheritance of GRTH and its heterogeneity. Elucidation of the etiology of GRTH has not only added a new means for the early diagnosis of the syndrome but provided new insights in the understanding of the mechanism of hormone action.

Diagnosis↗
PubMed1994

Demonstration of rapid light-induced advances and delays of the human circadian clock using hormonal phase markers.

To determine the magnitude and direction of phase shifts of human circadian rhythms occurring within 1 day after a single exposure to bright light, plasma thyrotropin, melatonin, and cortisol levels and body temperature were monitored for 38 h in 17 men who were each studied two times, once during continuous dim light conditions and once with light exposure. After a period of entrainment to a fixed sleep-wake cycle, a 3-h light pulse (5,000 lux) was presented under constant routine conditions, and the resultant phase shifts were measured, also under constant routine conditions, on the 1st day after pulse presentation. The phase shifts in response to light occurred within 24 h and were in the delaying direction for most of the nocturnal period, with the crossover to phase advances occurring approximately 1 h after the temperature minimum. Phase shifts averaged 1 h, with delays being larger than advances, and were achieved without significant changes in rhythm amplitude. The immediate response of the human circadian clock to a single 3-h light pulse is thus characteristic of "type 1" resetting.

Adult↗
PubMed1994

Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men.

To determine whether a single episode of physical activity is capable of inducing rapid phase shifts in human circadian rhythms, 17 subjects were studied two times under constant routine conditions, once in the absence of stimulus and once with a 3-h nighttime pulse of exercise interrupting the constant routine conditions. The profiles of plasma cortisol, thyrotropin (TSH), and melatonin and of body temperature were monitored continuously to derive estimations of circadian phase position. The phase shifts were measured on the 1st day after exercise exposure. The timing of the exercise period ranged from -5 h to +4 h around the time of the minimum body temperature rhythm. Nighttime exercise was associated with 1- to 2-h phase delays of both the melatonin and TSH rhythms, with the size of the delays tending to be smaller when the exercise was presented in the latter part of the nighttime period and in the early morning. These data demonstrate that nonphotic stimuli may exert phase-shifting effects on the human circadian pacemaker.

Adult↗
PubMed1994

Mutations of CpG dinucleotides located in the triiodothyronine (T3)-binding domain of the thyroid hormone receptor (TR) beta gene that appears to be devoid of natural mutations may not be detected because they are unlikely to produce the clinical phenotype of resistance to thyroid hormone.

Thyroid hormone receptor (TR) beta gene mutations identified in patients with resistance to thyroid hormone (RTH) revealed two clusters ("hot" areas) of mutations (RTHmut) in the triiodothyronine (T3)-binding domain. Furthermore, 45% of RTHmuts and 90% of recurring mutations are located in CpG dinucleotides ("hot spots"). To investigate why the region between the two hot areas lacks RTHmuts, we produced 10 artificial mutant TR beta s (ARTmut) in this "cold" region according to the hot spot rule (C-->T or G-->A substitutions in CpGs). The properties of ARTmuts were compared with those of six RTHmuts. Among all RTHmuts, R320H manifesting a mild form of RTH showed the least impairment of T3-binding affinity (Ka). In contrast, Ka was normal in six ARTmuts (group A), reduced to a lesser extent than R320H in three (group B), and one that was truncated (R410X) did not bind T3. All RTHmuts had impaired ability to transactivate T3-responsive elements and exhibited a strong dominant negative effect on cotransfected wild-type TR beta. Group B and A ARTmuts had minimally impaired or normal transactivation and weak or no dominant negative effect, respectively. R410X showed neither transactivation nor dominant negative effect. Natural mutations expected to occur in the cold region of TR beta should fail to manifest as RTH (group A) or should escape detection (group B) since the serum thyroid hormone levels required to compensate for the reduced binding affinity should be inferior to those found in subjects with R320H. R410X would manifest RTH only in the homozygote state. The cold region of the putative T3-binding domain is relatively insensitive to amino acid changes and, thus, may not be involved in a direct interaction with T3.

Animals↗
PubMed1994

A new point mutation (C446R) in the thyroid hormone receptor-beta gene of a family with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta (TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (+/- SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 +/- 21 vs. 108 +/- 13; total T3, 4.3 +/- 0.4 vs. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TR beta expressed in Cos-I cells did not bind T3 (Ka of C446R/wild-type, < 0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild-type TR beta.

Adolescent↗
PubMed1994

Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of tissues to thyroid hormone. The clinical manifestations are variable and 46-50% of children with RTH have attention deficit hyperactivity disorder (ADD). We present a new family with RTH (F120) found to have a mutation R316H in the thyroid hormone receptor beta (TR beta) gene identical for that reported in an unrelated family. Assignment of the mutant allele and haplotyping based on CA repeat polymorphism were done on 16 family members. Semistructured diagnostic interviews and psychometric testing were used to determine the psychiatric diagnosis of 12 family members by examiners blinded to the genotype. Three subjects were identified to have the R316H allele as well as mildly elevated free T4 index (168 +/- 12; normal range 77-135) and nonsuppressed TSH (4.1 +/- 1.7 mU/L). Only 2 of the subjects with RTH were found to have ADD, while one family member homozygous for the wild type TR beta and normal thyroid function tests also had ADD. Unaffected family members had higher full scale intelligence quotients (IQ) (93 +/- 7) than any of the 3 family members with RTH (77 +/- 5, p = 0.006). These data do not support the genetic linkage of ADD and RTH, but do suggest that RTH is associated with lower IQ scores that may confer a high likelihood of exhibiting ADD symptoms.

Adolescent↗