Papers by Samuel Refetoff
Journal of Endocrinological Investigation, 2019
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Journal of the Endocrine Society, 2021
Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X- chromosome-linked neurodevel... more Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X- chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transporter across cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as inability of standard biomarkers of neonatal screening to make an early diagnosis. Here, we report for the first time the ability to identify MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We measured T3, T4, and reverse T3 (rT3) levels in DBS samples obtained at birth in healthy neonates (n = 42) and neonates with genetically confirmed diagnosis of MCT8 deficiency (n = 6). T3, rT3 and T4 levels were measured in 8 mm diameter DBS samples using liquid chromatography-tandem mass spectrometry. Results: Mean ± SD level of T3 tended to be higher in the MCT8 group than that in healthy neonates (0.941 ± 0.183 ng/mL vs. 0.742 ± 0.195 ng/mL, p = 0.0525). More importan...
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Endocrinology, Jun 15, 2017
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Endocrine Abstracts, Oct 20, 2017
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Molecular Endocrinology, Feb 1, 2008
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The Journal of Clinical Endocrinology and Metabolism, Mar 1, 1999
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European Thyroid Journal, 2022
Objective Bi-allelic loss-of-function mutations in TSHB, encoding the beta subunit of thyroid-sti... more Objective Bi-allelic loss-of-function mutations in TSHB, encoding the beta subunit of thyroid-stimulating hormone (TSH), cause congenital hypothyroidism. Homozygosity for the TSHB p.R75G variant, previously described in South Asian individuals, does not alter TSH function but abrogates its detection by some immune detection-based platforms, leading to erroneous diagnosis of hyperthyroidism. We set out to identify and determine the carrier rate of the p.R75G variant among clinically euthyroid Bene Israel Indian Jews, to examine the possible founder origin of this variant worldwide, and to determine the phenotypic effects of its heterozygosity. Design Molecular genetic studies of Bene Israel Jews and comparative studies with South Asian cohort. Methods TSHB p.R75G variant tested by Sanger sequencing and restriction fragment length polymorphism (RFLP). Haplotype analysis in the vicinity of the TSHB gene performed using SNP arrays. Results Clinically euthyroid individuals with low or un...
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The thyroid gland captures iodide in order to synthesize hormones that act on almost all tissues ... more The thyroid gland captures iodide in order to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common disorder in humans and is not always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, functional human thyroid organoids could pave the way to explore new therapeutic approaches. Here we report the first transplantable thyroid organoids derived from human embryonic stem cells capable of restoring plasma thyroid hormone to athyreotic mice as a proof of concept for future therapeutic development.
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American Journal of Clinical Pathology, 2021
Objectives Thyroid hormone analog 3,5,3'-triiodothyroacetic acid (TRIAC) is effective in redu... more Objectives Thyroid hormone analog 3,5,3'-triiodothyroacetic acid (TRIAC) is effective in reducing the hypermetabolism in monocarboxylate transporter 8 (MCT8)–deficient individuals. Because of the structural similarity between TRIAC and 3,3',5'-triiodothyronine (T3), we sought to investigate the degree of cross-reactivity of TRIAC with various commercially available total and free T3 assays. Methods Varying concentrations (50-1,000 ng/dL) of TRIAC (Sigma Aldrich) were added to pooled serum and assayed for total T3 (TT3) and free T3 (FT3) on the following platforms: e602 (Roche Diagnostics), Architect (Abbott Diagnostics), Centaur (Siemens Healthcare Diagnostics), IMMULITE (Siemens Healthcare Diagnostics), DxI (Beckman Coulter), and Vitros (Ortho Clinical Diagnostics). TT3 competition assay with TRIAC was performed by adding increasing amounts of T3 to pooled serum samples that contained a constant concentration of TRIAC (250 ng/dL). Results Significant overestimation of T...
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Thyroid, 2021
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Journal of the Endocrine Society, 2020
Iodothyronine deiodinases (Ds) mediate thyroid hormone (TH) action. They catalyze triiodothyronin... more Iodothyronine deiodinases (Ds) mediate thyroid hormone (TH) action. They catalyze triiodothyronine (T3) production and degradation via, respectively; outer (ORD) and inner (IRD) ring deiodination. Type 1 D (D1) has a relatively high Km for substrates thyroxine (T4) and reverse T3 (rT3), catalyzes both ORD and IRD and is inhibited by propylthiouracil (PTU). Although no mutations in DIO1 gene have been reported so far in humans, based on the D1-deficient C3H mouse and the heterozygous Dio1 knockout mice, the expected phenotype of D1 loss-of-function is higher serum rT3 and slightly elevated T4. Our objective was to identify new gene defects causing unexplained and discrepant thyroid function tests using whole-exome sequencing (WES). Exons and splice sites are captured with Agilent SureSelectXT and sequenced in Illumina HiSeq2500. Data are analyzed with BWA, GATK, and ANNOVAR applications for alignment, variant calling and annotation, respectively. Sanger sequencing is used to confirm ...
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Thyroid, 2020
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The Journal of Clinical Endocrinology & Metabolism, 2019
Context Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worl... more Context Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan. Objective To investigate the molecular basis of CH in Sudanese families. Design Clinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing. Setting University research center. Patients Twenty-six Sudanese families with CH. Intervention Clinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations. Results Mutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mut...
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American Journal of Physiology-Endocrinology and Metabolism, 1994
To determine the magnitude and direction of phase shifts of human circadian rhythms occurring wit... more 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...
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American Journal of Physiology-Endocrinology and Metabolism, 1994
To determine whether a single episode of physical activity is capable of inducing rapid phase shi... more 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-shi...
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Thyroid : official journal of the American Thyroid Association, Jan 30, 2018
Dyshormonogenic congenital hypothyroidism (CH) generally results from biallelic defects in thyroi... more Dyshormonogenic congenital hypothyroidism (CH) generally results from biallelic defects in thyroid hormone synthesis genes. Whole exome sequencing (WES) allows easier identification of multiple gene defects. We present 2 Sudanese families with CH resulting from oligogenic defects identified by WES. In Family 1, the proposita with CH and goiter was heterozygous for three TPO, one TG and one DUOX2 mutations, including three novel variants inherited from both parents. In Family 2, two brothers with psychomotor delay and goiter were homozygous for digenic mutations in the DUOX2 and DUOX1 genes while their asymptomatic parents were heterozygous. Accumulation of pathogenic mutations may contribute to CH.
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Pediatric Medicine, 2018
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Best Practice & Research Clinical Endocrinology & Metabolism, 2017
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Endocrinology, 2016
Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisys... more Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisystemic lysosomal storage disease caused by defective transmembrane cystine transporter, cystinosin (CTNS gene). We recently demonstrated in Ctns−/− mice that altered thyroglobulin biosynthesis associated with endoplasmic reticulum stress, combined with defective lysosomal processing, caused hypothyroidism. In Ctns−/− kidney, hematopoietic stem cell (HSC) transplantation provides long-term functional and structural protection. Tissue repair involves transfer of cystinosin-bearing lysosomes from HSCs differentiated as F4/80 macrophages into deficient kidney tubular cells, via tunneling nanotubes that cross basement laminae. Here we evaluated the benefit of HSC transplantation for cystinotic thyroid and investigated the underlying mechanisms. HSC engraftment in Ctns−/− thyroid drastically decreased cystine accumulation, normalized the TSH level, and corrected the structure of a large fractio...
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Papers by Samuel Refetoff