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Marc-Olivier Turgeon, Tanya L Silander, Denica Doycheva, Xiao-Hui Liao, Marc Rigden, Luisina Ongaro, Xiang Zhou, Sjoerd D Joustra, Jan M Wit, Mike G Wade, Heike Heuer, Samuel Refetoff, Daniel J Bernard
Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in thyrotropin (TSH)-producing thyrotrope cells of the anterior pituitary gland. The protein is cotranslationally cleaved, with only its C-terminal domain (CTD) being trafficked to the plasma membrane. Most intragenic IGSF1 mutations in humans map to the CTD. In this study, we used CRISPR-Cas9 to introduce a loss-of-function mutation into the IGSF1-CTD in mice...
April 1, 2017: Endocrinology
Corina Neamţu, Claudiu Ţupea, Diana Păun, Anca Hoisescu, Adina Ghemigian, Samuel Refetoff, Chutintorn Sriphrapradang
Thyroid hormones (TH) exert their actions by binding nuclear receptors alpha (TRα1) and beta (TRß1 and TRß2). Resistance to thyroid hormone (RTH) is a clinical syndrome with various clinical manifestations, its hallmark being decreased tissue sensitivity to the action of thyroid hormones. We report the case of a family harbouring a novel TRß mutation. Sequencing of the TRβ gene revealed a single nucleotide substitution-C to G in codon 340: glutamine was replaced by glutamic acid. The clinical picture and biochemical and hormonal panel showed significant differences within the family, despite their sharing the same mutation...
October 2016: Hormones: International Journal of Endocrinology and Metabolism
Panudda Srichomkwun, Neal H Scherberg, Jasminka Jakšić, Samuel Refetoff
OBJECTIVE: Assay interference could be the cause of abnormal thyroid function tests. Early recognition prevents inappropriate patient management. The objective of this report is to present a case with discordant thyroid function tests in different thyroid assay platforms due to thyroid autoantibodies. METHODS: We present a case her family, laboratory data and methods that investigate immunoassay interference. RESULTS: A 21-year-old woman with autoimmune thyroid disease was treated for hypothyroidism with levothyroxine and noted to have elevated total and free thyroxine, free triiodothyronine but normal thyroid-stimulating hormone...
2017: AACE Clinical Case Reports
Panudda Srichomkwun, Junta Takamatsu, Deborah A Nickerson, Michael J Bamshad, Jessica X Chong, Samuel Refetoff
Resistance to thyrotropin (TSH) (RTSH; defined by elevated TSH and a normal or hypoplastic thyroid gland) can be caused by mutations in genes encoding the TSH receptor and PAX8, and it has been linked to a locus on chromosome 15. In two nonconsanguineous families with nongoitrous euthyroid hyperthyrotropinemia, typical of the RTSH phenotype, exome analysis identified five rare DUOX2 gene variants (p.A649E, p.P1391A, p.R885L, p.G488R, and p.SF965-6SfsX29) found to be pathogenic. This form of nongoitrous dyshormonogenesis masquerades both clinically and biochemically as RTSH...
January 2017: Thyroid: Official Journal of the American Thyroid Association
Chutintorn Sriphrapradang, Panudda Srichomkwun, Samuel Refetoff, Sunee Mamanasiri
A patient is reported with resistance to thyroid hormone beta caused by a novel THRB gene mutation and coexisting pituitary microadenoma. A 41-year-old Thai woman presented with elevated serum thyroid hormone levels and non-suppressed thyrotropin (TSH). Magnetic resonance imaging showed a 4 mm × 2 mm pituitary adenoma. Five of her relatives had similar thyroid tests abnormalities, but a sister had Graves' disease. Thyroperoxidase and thyroglobulin antibodies were positive in all affected family members, except for the proband's 4...
December 2016: Thyroid: Official Journal of the American Thyroid Association
Zineb Eskalli, Younes Achouri, Stephan Hahn, Marie-Christine Many, Julie Craps, Samuel Refetoff, Xiao-Hui Liao, Jacques E Dumont, Jacqueline Van Sande, Bernard Corvilain, Françoise Miot, Xavier De Deken
BACKGROUND: The dual oxidases (Duox) are involved in hydrogen peroxide generation, which is essential for thyroid hormone synthesis, and therefore they are markers of thyroid function. During inflammation, cytokines upregulate DUOX gene expression in the airway and the intestine, suggesting a role for these proteins in innate immunity. It was previously demonstrated that interleukin-4 (IL-4) upregulates DUOX gene expression in thyrocytes. Although the role of IL-4 in autoimmune thyroid diseases has been studied extensively, the effects of IL-4 on thyroid physiology remain largely unknown...
October 2016: Thyroid: Official Journal of the American Thyroid Association
Hideyuki Iwayama, Xiao-Hui Liao, Lyndsey Braun, Soledad Bárez-López, Brian Kaspar, Roy E Weiss, Alexandra M Dumitrescu, Ana Guadaño-Ferraz, Samuel Refetoff
BACKGROUND: MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. This proof-of-concept study examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice (Mct8KO). METHODS: AAV9 vectors delivering long and/or short hMCT8 protein isoforms or an empty vector were injected intravenously (IV) and/or intracerebroventricularly (ICV) into postnatal day 1 Mct8KO and wild type (Wt) mice...
September 2016: Thyroid: Official Journal of the American Thyroid Association
Panudda Srichomkwun, Osnat Admoni, Samuel Refetoff, Liat de Vries
BACKGROUND: Congenital hypothyroidism (CH) is a common endocrine disorder in newborns. The cause of CH is thyroid dysgenesis in 80-85% of patients. Paired box gene 8 (PAX8) is a thyroid transcription factor that plays an important role in thyroid organogenesis and development. To date, 22 different PAX8 gene mutations have been reported. METHODS: Four generations of a Hungarian Jewish family were affected, and in the 3 generations studied, 9 males and 4 females were affected and 3 first-degree relatives were unaffected...
2016: Hormone Research in Pædiatrics
Mylah Villacorte, Anne-Sophie Delmarcelle, Manon Lernoux, Mahé Bouquet, Pascale Lemoine, Jennifer Bolsée, Lieve Umans, Susana Chuva de Sousa Lopes, Patrick Van Der Smissen, Takako Sasaki, Guido Bommer, Patrick Henriet, Samuel Refetoff, Frédéric P Lemaigre, An Zwijsen, Pierre J Courtoy, Christophe E Pierreux
Thyroid follicles, the functional units of the thyroid gland, are delineated by a monolayer of thyrocytes resting on a continuous basement membrane. The developmental mechanisms of folliculogenesis, whereby follicles are formed by the reorganization of a non-structured mass of non-polarized epithelial cells, are largely unknown. Here we show that assembly of the epithelial basement membrane is crucial for folliculogenesis and is controlled by endothelial cell invasion and by BMP-Smad signaling in thyrocytes...
June 1, 2016: Development
Izuki Amano, Yusuke Takatsuru, Syutaro Toya, Asahi Haijima, Toshiharu Iwasaki, Helmut Grasberger, Samuel Refetoff, Noriyuki Koibuchi
BACKGROUND: Thyroid hormone (TH) plays a key role in the developing brain, including the cerebellum. TH deficiency induces organizational changes of the cerebellum, causing cerebellar ataxia. However, the mechanisms causing these abnormalities are poorly understood. Various animal models have been used to study the mechanism. Lacking dual oxidase (DUOX) and its maturation factor (DUOXA) are major inducers of congenital hypothyroidism. Thus, this study examined the organizational changes of the cerebellum using knockout mice of the Duoxa gene (Duoxa-/-)...
May 2016: Thyroid: Official Journal of the American Thyroid Association
Kenji Ohba, Melvin Khee-Shing Leow, Brijesh Kumar Singh, Rohit Anthony Sinha, Ronny Lesmana, Xiao-Hui Liao, Sujoy Ghosh, Samuel Refetoff, Judy Chia Ghee Sng, Paul Michael Yen
Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult male mice treated either with a single T3 (20 μg per 100 g body weight) injection (acute T3) or daily injections for 14 days (chronic T3) followed by 10 days of withdrawal. Gene expression arrays from livers harvested at these time points showed that among positively-regulated target genes, 320 were stimulated acutely and 429 chronically by T3...
April 2016: Endocrinology
H P Gaide Chevronnay, V Janssens, P Van Der Smissen, C J Rocca, X H Liao, S Refetoff, C E Pierreux, S Cherqui, P J Courtoy
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...
April 2016: Endocrinology
Theodora Pappa, Alfonso Massimiliano Ferrara, Samuel Refetoff
Thyroid hormones (TH) are bound to three major serum transport proteins, thyroxine-binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). TBG has the strongest affinity for TH, whereas HSA is the most abundant protein in plasma. Individuals harboring genetic variations in TH transport proteins present with altered thyroid function tests, but are clinically euthyroid and do not require treatment. Clinical awareness and early recognition of these conditions are important to prevent unnecessary therapy with possible untoward effects...
October 2015: Best Practice & Research. Clinical Endocrinology & Metabolism
Alfonso Massimiliano Ferrara, Xiao-Hui Liao, Honggang Ye, Roy E Weiss, Alexandra M Dumitrescu, Samuel Refetoff
Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH...
November 2015: Endocrinology
Theodora Pappa, Jesper Johannesen, Neal Scherberg, Maricel Torrent, Alexandra Dumitrescu, Samuel Refetoff
BACKGROUND: Thyrotropin (TSH) deficiency caused by TSHβ gene mutations is a rare form of congenital central hypothyroidism. Nine different TSHβ gene mutations have been reported, all with clinical manifestations. The aim was to identify the genetic cause of undetectable TSH levels in two siblings with clinical euthyroidism. METHODS: Two brothers born to consanguineous Pakistani parents presented with undetectable serum TSH but normal iodothyronine concentrations and no clinical signs of hypothyroidism...
August 2015: Thyroid: Official Journal of the American Thyroid Association
H P Gaide Chevronnay, V Janssens, P Van Der Smissen, X H Liao, Y Abid, N Nevo, C Antignac, S Refetoff, S Cherqui, C E Pierreux, P J Courtoy
Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold)...
June 2015: Endocrinology
Yardena Tenenbaum-Rakover, Shlomo Almashanu, Ora Hess, Osnat Admoni, Ahmad Hag-Dahood Mahameed, Naama Schwartz, Stavit Allon-Shalev, Dani Bercovich, Samuell Refetoff
BACKGROUND: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations...
March 2015: Thyroid: Official Journal of the American Thyroid Association
Keisuke Ikegami, Xiao-Hui Liao, Yuta Hoshino, Hiroko Ono, Wataru Ota, Yuka Ito, Taeko Nishiwaki-Ohkawa, Chihiro Sato, Ken Kitajima, Masayuki Iigo, Yasufumi Shigeyoshi, Masanobu Yamada, Yoshiharu Murata, Samuel Refetoff, Takashi Yoshimura
Thyroid-stimulating hormone (TSH; thyrotropin) is a glycoprotein secreted from the pituitary gland. Pars distalis-derived TSH (PD-TSH) stimulates the thyroid gland to produce thyroid hormones (THs), whereas pars tuberalis-derived TSH (PT-TSH) acts on the hypothalamus to regulate seasonal physiology and behavior. However, it had not been clear how these two TSHs avoid functional crosstalk. Here, we show that this regulation is mediated by tissue-specific glycosylation. Although PT-TSH is released into the circulation, it does not stimulate the thyroid gland...
November 6, 2014: Cell Reports
Alfonso Massimiliano Ferrara, Theodora Pappa, Jiao Fu, Christopher D Brown, April Peterson, Lars C Moeller, Kathleen Wyne, Kevin P White, Anna Pluzhnikov, Vassily Trubetskoy, Marcelo Nobrega, Roy E Weiss, Alexandra M Dumitrescu, Samuel Refetoff
CONTEXT: T4-binding globulin (TBG), a protein secreted by the liver, is the main thyroid hormone (TH) transporter in human serum. TBG deficiency is characterized by reduced serum TH levels, but normal free TH and TSH and absent clinical manifestations. The inherited form of TBG deficiency is usually due to a mutation in the TBG gene located on the X-chromosome. OBJECTIVE: Among the 75 families with X-chromosome-linked TBG deficiency identified in our laboratory, no mutations in the TBG gene were found in four families...
January 2015: Journal of Clinical Endocrinology and Metabolism
Daniela López-Espíndola, Carmen Morales-Bastos, Carmen Grijota-Martínez, Xiao-Hui Liao, Dorit Lev, Ella Sugo, Charles F Verge, Samuel Refetoff, Juan Bernal, Ana Guadaño-Ferraz
CONTEXT: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. OBJECTIVE: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. DESIGN: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy...
December 2014: Journal of Clinical Endocrinology and Metabolism
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