138 results on '"Chatterjee VK"'
Search Results
2. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland
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Nicholas, AK, Jaleel, S, Lyons, G, Schoenmakers, E, Dattani, MT, Crowne, E, Bernhard, B, Kirk, J, Roche, EF, Chatterjee, VK, Schoenmakers, N, Schoenmakers, Erik [0000-0003-0674-8282], Chatterjee, Krishna [0000-0002-2654-8854], Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository
- Subjects
Male ,Heterozygote ,Delayed Diagnosis ,Homozygote ,Infant, Newborn ,Original Articles ,Sequence Analysis, DNA ,Thyrotropin, beta Subunit ,United Kingdom ,Pedigree ,Editor's Choice ,Neonatal Screening ,Hypothyroidism ,Congenital Hypothyroidism ,Humans ,Original Article ,Female ,Ireland - Abstract
Summary Objective Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH‐based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. Design, Patients and Measurements Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). Results Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4‐kB TSHB deletion (kindred 2, c.1‐4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. Conclusions This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine‐binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.
- Published
- 2016
3. Mild cold effects on hunger, food intake, satiety and skin temperature in humans
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Langeveld, M, Tan, CY, Soeters, MR, Virtue, S, Ambler, GK, Watson, LPE, Murgatroyd, PR, Chatterjee, VK, Vidal-Puig, A, Amsterdam Gastroenterology Endocrinology Metabolism, Endocrinology, Chatterjee, Krishna [0000-0002-2654-8854], Vidal-Puig, Antonio [0000-0003-4220-9577], and Apollo - University of Cambridge Repository
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lcsh:RC648-665 ,Research ,thermogenesis ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Cold ,hunger - Abstract
BACKGROUND: Mild cold exposure increases energy expenditure and can influence energy balance, but at the same time it does not increase appetite and energy intake.OBJECTIVE: To quantify dermal insulative cold response, we assessed thermal comfort and skin temperatures changes by infrared thermography.METHODS: We exposed healthy volunteers to either a single episode of environmental mild cold or thermoneutrality. We measured hunger sensation and actual free food intake. After a thermoneutral overnight stay, five males and five females were exposed to either 18°C (mild cold) or 24°C (thermoneutrality) for 2.5 h. Metabolic rate, vital signs, skin temperature, blood biochemistry, cold and hunger scores were measured at baseline and for every 30 min during the temperature intervention. This was followed by an ad libitum meal to obtain the actual desired energy intake after cold exposure.RESULTS: We could replicate the cold-induced increase in REE. But no differences were detected in hunger, food intake, or satiety after mild cold exposure compared with thermoneutrality. After long-term cold exposure, high cold sensation scores were reported, which were negatively correlated with thermogenesis. Skin temperature in the sternal area was tightly correlated with the increase in energy expenditure.CONCLUSIONS: It is concluded that short-term mild cold exposure increases energy expenditure without changes in food intake. Mild cold exposure resulted in significant thermal discomfort, which was negatively correlated with the increase in energy expenditure. Moreover, there is a great between-subject variability in cold response. These data provide further insights on cold exposure as an anti-obesity measure.
- Published
- 2016
4. A Novel Thyrotropin-Releasing Hormone Receptor Missense Mutation (P81R) in Central Congenital Hypothyroidism
- Author
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Koulouri, O, Nicholas, AK, Schoenmakers, E, Mokrosinski, J, Lane, F, Cole, T, Kirk, J, Farooqi, IS, Chatterjee, VK, Gurnell, M, Schoenmakers, N, Schoenmakers, Erik [0000-0003-0674-8282], Mokrosinski, Jacek [0000-0001-5008-0457], Farooqi, Ismaa [0000-0001-7609-3504], Chatterjee, Krishna [0000-0002-2654-8854], Gurnell, Mark [0000-0001-5745-6832], Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository
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endocrine system ,HEK293 Cells ,Receptors, Thyrotropin-Releasing Hormone ,Congenital Hypothyroidism ,Infant, Newborn ,Mutation, Missense ,Humans ,Female ,Special Features - Abstract
CONTEXT: Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH β subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene. CASE DESCRIPTION: A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2. CONCLUSIONS: Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.
- Published
- 2016
5. Rosiglitazone increases indexes of stearoyl-CoA desaturase activity in humans: link to insulin sensitization and the role of dominant-negative mutation in peroxisome proliferator-activated receptor-gamma
- Author
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Risérus, U, Tan, GD, Fielding, BA, Neville, MJ, Currie, J, Savage, DB, Chatterjee, VK, Frayn, KN, O'Rahilly, S, and Karpe, F
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congenital, hereditary, and neonatal diseases and abnormalities ,hemic and lymphatic diseases - Abstract
Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and delta6- and delta5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and delta5-desaturase but not delta6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPARgamma carrier, SCD and delta5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPARgamma mutation supports a pivotal role of PPARgamma function in SCD regulation.
- Published
- 2016
6. Neonatal thyrotoxicosis and maternal infertility in thyroid hormone resistance due to a mutation in the TRbeta gene (M313T)
- Author
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Blair, JC, Mohan, U, Larcher, VF, Rajanayagam, O, Burrin, JM, Perry, LA, Grossman, AB, Chatterjee, VK, and Savage, MO
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endocrine system ,hormones, hormone substitutes, and hormone antagonists - Abstract
We report two unusual cases of resistance to thyroid hormone (RTH) in one family. The first case, a male infant, had clinical features of thyrotoxicosis in the neonatal period. In the fourth week of life weight gain was poor despite a daily intake of standard infant formula almost double the infant's estimated requirements. At this time serum free T4 (fT4) was 60.7 pmol/l (Normal range [NR] 11-25 pmol/l) and TSH was inappropriately normal at 1.8 mU/l (NR 0.3-4.0 mU/l). The infant responded clinically and biochemically to propylthiouracil (PTU) at a dose of 10 mg/kg/day. Following 27 days of treatment serum fT4 was 22.6 pmol/l and TSH had risen to 24.9 mU/l. As the infant was thriving treatment was discontinued. The infant, now aged 6 months old, remains clinically euthyroid and developmentally normal off treatment. The infant's mother, from whom he had inherited a mutation of the thyroid receptor beta (TRbeta) gene (M313T), presented earlier with secondary infertility and clinical features of thyrotoxicosis. Treatment with PTU restored her fertility and she spontaneously conceived. In the subsequent pregnancy, clinical and biochemical features of RTH improved, and she gave birth to a small but healthy female infant. In the next pregnancy, resulting in the birth of the affected male infant, clinical and biochemical features of RTH worsened, and high doses of PTU were required to maintain a clinically euthyroid state. To our knowledge, these are the first case reports of RTH associated with added features of a hypermetabolic state in infancy and secondary infertility.
- Published
- 2016
7. Dehydroepiandrosterone replacement therapy
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Gurnell, EM, primary and Chatterjee, VK, additional
- Published
- 2001
- Full Text
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8. St John's wort, a herbal antidepressant, activates the steroid X receptor
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Wentworth, JM, primary, Agostini, M, additional, Love, J, additional, Schwabe, JW, additional, and Chatterjee, VK, additional
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- 2000
- Full Text
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9. HIV protease inhibitors block human preadipocyte differentiation, but not via the PPARgamma/RXR heterodimer
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Wentworth, JM, primary, Burris, TP, additional, and Chatterjee, VK, additional
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- 2000
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10. Thyroid in 2012: Advances in thyroid development, hormone action and neoplasia.
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Chatterjee VK and Chatterjee, V Krishna K
- Abstract
In 2012, we learned that functional thyroid tissue can be generated in vitro, and that thyroid hormones stimulate autophagy. Patients with defects in TRα have been identified, and di-iodothyropropionic acid has been shown to ameliorate MCT8 deficiency. Finally, we found that gene expression profiling can identify benign thyroid nodules. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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11. Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism
- Author
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Aycan, Z, Cangul, H, Muzza, M, Bas, VN, Fugazzola, L, Chatterjee, VK, Persani, L, and Schoenmakers, N
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Male ,Genotype ,Infant, Newborn ,Genetic Variation ,Infant ,NADPH Oxidases ,Thyroid Function Tests ,Dual Oxidases ,Severity of Illness Index ,3. Good health ,Pedigree ,Cohort Studies ,Phenotype ,Codon, Nonsense ,Congenital Hypothyroidism ,Humans ,Female ,Genetic Predisposition to Disease ,Retrospective Studies - Abstract
Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the TPO-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic Congenital Hypothyroidism (CH) which may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (eg dietary iodine) and oligogenic modifiers (eg variants in the homologous NADPH-oxidase DUOX1). However, loss of function mutations in DUOX1 have not hitherto been described and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: TSH >100 µU/mL (reference range, RR: 0.5-6.3), P1: Free T4 (FT4) C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43) which segregates with CH in this kindred. Conclusion: This is the first report of digenic mutations in DUOX1 and DUOX2 in association with CH and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a novel digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically-ascertained CH.
12. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland
- Author
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Nicholas, AK, Jaleel, S, Lyons, G, Schoenmakers, E, Dattani, MT, Crowne, E, Bernhard, B, Kirk, J, Roche, EF, Chatterjee, VK, and Schoenmakers, N
- Subjects
Male ,Heterozygote ,Delayed Diagnosis ,Homozygote ,Infant, Newborn ,Sequence Analysis, DNA ,Thyrotropin, beta Subunit ,United Kingdom ,3. Good health ,Pedigree ,Neonatal Screening ,Hypothyroidism ,Congenital Hypothyroidism ,Humans ,Female ,Ireland - Abstract
OBJECTIVE: Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH-based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder. DESIGN, PATIENTS AND MEASUREMENTS: Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT). RESULTS: Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4-kB TSHB deletion (kindred 2, c.1-4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth. CONCLUSIONS: This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine-binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae.
13. Isolated deficiency of follicle-stimulating hormone re-revisited.
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Matthews C and Chatterjee VK
- Published
- 1997
14. The role of G protein alpha 11 in calcium and glucose homeostasis
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Glück, AK, Russell, RGC, Chatterjee, VK, Thakker, RV, and Lines, KE
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Endocrinology ,Metabolism ,Genetics ,Cell signalling - Abstract
Guanine nucleotide-binding (G) proteins act as molecular switches to transduce stimuli received by G protein-coupled receptors (GPCRs) into intracellular responses. For example, Gα11 mediates signalling by the calcium-sensing receptor (CaSR), a class C GPCR, to regulate calcium homeostasis. Germline CaSR and Gα11 inactivating and activating mutations cause calcitropic disorders such as familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH) types-1 and -2, respectively. In addition, non-calcitropic disorders may also occur, e.g. Nuf mice (model for ADH1) have impaired glucose metabolism. This thesis aims to: identify and characterise rare Gα11 variants from online databases; investigate glucose metabolism of Dsk7 mice (model for ADH2); study CaSR signalling differences between Gα11 and the closely related Gαq; and explore CaSR functional selectivity and G protein biased signalling. My analysis revealed novel Gα11 variants that cause CaSR signalling abnormalities in vitro and are associated with hypercalcaemia in patients. Moreover, some Gα11 variants also disrupted signalling by prototypical class A GPCRs and promoted biased and promiscuous signalling. In contrast, Gα11 gain-of-function did not impair glucose homeostasis or pancreatic islet architecture in Dsk7 mice, indicating that other G proteins may be involved in these non-calcitropic CaSR functions. Gαq mutations were not found in patients with FHH or ADH, and engineering FHH2- and ADH2-associated Gα11 mutations in Gαq did not alter Gαq function, thereby highlighting functional differences between them. Analysis of CaSR functional selectivity showed that the CaSR is a promiscuous receptor which activates eight G proteins and that clinically approved CaSR allosteric modulators can promote biased signalling. In summary, my thesis illustrates the importance of Gα11 for CaSR signalling, demonstrated by identification of additional FHH2 mutants, and that Gα11 mutations disrupt signalling by other GPCRs, thereby possibly leading to wider effects. Additionally, CaSR biased-signalling highlights the importance of G proteins other than Gα11 for this GPCR.
- Published
- 2021
15. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis.
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Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, Weetman A, Hale G, Chatterjee VK, Waldmann H, and Compston A
- Published
- 1999
- Full Text
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16. Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β.
- Author
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Wejaphikul K, Groeneweg S, Hilhorst-Hofstee Y, Chatterjee VK, Peeters RP, Meima ME, and Visser WE
- Subjects
- Female, Humans, Mutation, Transcriptional Activation genetics, Thyroid Hormone Receptors alpha genetics, Thyroid Hormone Receptors beta genetics, Thyroid Hormone Resistance Syndrome genetics, Thyroxine genetics, Triiodothyronine genetics
- Abstract
Context: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity., Objective: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4., Methods: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed., Results: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4., Conclusions: Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling.
- Published
- 2019
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17. Immune reconstitution after alemtuzumab therapy for multiple sclerosis triggering Graves' orbitopathy: a case series.
- Author
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Roos JCP, Moran C, Chatterjee VK, Jones J, Coles A, and Murthy R
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- Adolescent, Adult, Autoantibodies blood, Disease Progression, Enzyme-Linked Immunosorbent Assay, Female, Graves Ophthalmopathy diagnostic imaging, Graves Ophthalmopathy immunology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis immunology, Receptors, Thyrotropin immunology, Recurrence, Retrospective Studies, Risk Factors, Alemtuzumab adverse effects, Antineoplastic Agents, Immunological adverse effects, Graves Ophthalmopathy chemically induced, Immune Reconstitution, Multiple Sclerosis drug therapy
- Abstract
Alemtuzumab-a monoclonal antibody targeting the CD52 glycoprotein expressed by most mature leucocytes-effectively decreases relapse rate and disability progression in early, relapsing-remitting multiple sclerosis (MS). However, secondary autoimmune disorders complicate therapy in nearly 50% of treated patients, with Graves' disease being the most common. Rarely, thyroid eye disease (TED) ensues; only seven such cases have been reported. Our aim was to analyse the largest series of MS patients developing thyroid eye disease after alemtuzumab treatment. We performed a retrospective chart review of MS patients treated with alemtuzumab (1995-2018) and subsequently identified by their treating physicians as having developed TED and referred to our ophthalmology service. As an original trial centre for alemtuzumab, our hospital has treated approximately 162 MS patients with this novel therapy. In total, 71 (44%) developed thyroid dysfunction, most of whom (87%) developed Graves' disease, with ten (16%) referred for ophthalmological evaluation. Two developed active orbitopathy following radioiodine treatment; one occurred after cessation of anti-thyroid drug treatment. Three developed sight-threatening disease requiring systemic immunosuppression, with one refractory to multiple immunosuppressants. The remaining patients were treated conservatively. TSH-receptor antibody (TRAb) levels were significantly raised in all cases, when ascertained. We report sight-threatening as well as mild TED in MS patients after treatment with alemtuzumab. Endocrine instability, radioiodine treatment and positive TRAb are all likely risk factors. The data support at least 6-monthly biochemical and clinical assessment with a low threshold for referral to an ophthalmologist, particularly for those with higher TRAb levels who may be at greater risk of orbitopathy.
- Published
- 2019
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18. Role of Leucine 341 in Thyroid Hormone Receptor Beta Revealed by a Novel Mutation Causing Thyroid Hormone Resistance.
- Author
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Wejaphikul K, Groeneweg S, Dejkhamron P, Unachak K, Visser WE, Chatterjee VK, Visser TJ, Meima ME, and Peeters RP
- Abstract
Leucine 341 has been predicted from crystal structure as an important residue for thyroid hormone receptor beta (TRβ) function, but this has never been confirmed in functional studies. Here, a novel p.L341V mutation as a cause of resistance to TRβ is described, suggesting an important role for L341 in TRβ function. In silico and in vitro studies confirmed that substituting L341 with valine and other non-polar amino acids impairs sensitivity of TRβ for triiodothyronine to various degrees, depending on their side-chain size and orientation.
- Published
- 2018
- Full Text
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19. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism.
- Author
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Cangul H, Liao XH, Schoenmakers E, Kero J, Barone S, Srichomkwun P, Iwayama H, Serra EG, Saglam H, Eren E, Tarim O, Nicholas AK, Zvetkova I, Anderson CA, Frankl FEK, Boelaert K, Ojaniemi M, Jääskeläinen J, Patyra K, Löf C, Williams ED, Soleimani M, Barrett T, Maher ER, Chatterjee VK, Refetoff S, and Schoenmakers N
- Subjects
- Adult, Animals, Child, Child, Preschool, Codon, Nonsense, Congenital Hypothyroidism diagnosis, DNA Mutational Analysis, Female, Goiter congenital, Goiter diagnosis, HEK293 Cells, Homozygote, Humans, Male, Mice, Mice, Knockout, Middle Aged, Pedigree, Thyroid Gland pathology, Exome Sequencing, Antiporters genetics, Congenital Hypothyroidism genetics, Goiter genetics, Sulfate Transporters genetics
- Abstract
Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.
- Published
- 2018
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20. Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab.
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Casey RT, Giger O, Seetho I, Marker A, Pitfield D, Boyle LH, Gurnell M, Shaw A, Tischkowitz M, Maher ER, Chatterjee VK, Janowitz T, Mells G, Corrie P, and Challis BG
- Subjects
- Adrenal Cortex Neoplasms metabolism, Adrenal Cortex Neoplasms pathology, Adrenocortical Carcinoma metabolism, Adrenocortical Carcinoma pathology, Antineoplastic Agents, Immunological therapeutic use, Brain Neoplasms genetics, Brain Neoplasms pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Disease Progression, Fatal Outcome, Female, Humans, Middle Aged, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary pathology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Adrenal Cortex Neoplasms drug therapy, Adrenocortical Carcinoma drug therapy, Antibodies, Monoclonal, Humanized therapeutic use, Brain Neoplasms metabolism, Colorectal Neoplasms metabolism, Hydrocortisone metabolism, Neoplastic Syndromes, Hereditary metabolism
- Abstract
Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC., Case Report: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure., Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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21. Adult-onset hyperinsulinaemic hypoglycaemia in clinical practice: diagnosis, aetiology and management.
- Author
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Challis BG, Powlson AS, Casey RT, Pearson C, Lam BY, Ma M, Pitfield D, Yeo GSH, Godfrey E, Cheow HK, Chatterjee VK, Carroll NR, Shaw A, Buscombe JR, and Simpson HL
- Abstract
Objective: In adults with hyperinsulinaemic hypoglycaemia (HH), in particular those with insulinoma, the optimal diagnostic and management strategies remain uncertain. Here, we sought to characterise the biochemical and radiological assessment, and clinical management of adults with HH at a tertiary centre over a thirteen-year period., Design: Clinical, biochemical, radiological and histological data were reviewed from all confirmed cases of adult-onset hyperinsulinaemic hypoglycaemia at our centre between 2003 and 2016. In a subset of patients with stage I insulinoma, whole-exome sequencing of tumour DNA was performed., Results: Twenty-nine patients were identified (27 insulinoma, including 6 subjects with metastatic disease; 1 pro-insulin/GLP-1 co-secreting tumour; 1 activating glucokinase mutation). In all cases, hypoglycaemia (glucose ≤2.2 mmol/L) was achieved within 48 h of a supervised fast. At fast termination, subjects with stage IV insulinoma had significantly higher insulin, C-peptide and pro-insulin compared to those with insulinoma staged I-IIIB. Preoperative localisation of insulinoma was most successfully achieved with EUS. In two patients with inoperable, metastatic insulinoma, peptide receptor radionuclide therapy (PRRT) with
177 Lu-DOTATATE rapidly restored euglycaemia and lowered fasting insulin. Finally, in a subset of stage I insulinoma, whole-exome sequencing of tumour DNA identified the pathogenic Ying Yang-1 ( YY1 ) somatic mutation (c.C1115G/p.T372R) in one tumour, with all tumours exhibiting a low somatic mutation burden., Conclusion: Our study highlights, in particular, the utility of the 48-h fast in the diagnosis of insulinoma, EUS for tumour localisation and the value of PRRT therapy in the treatment of metastatic disease., (© 2017 The authors.)- Published
- 2017
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22. Digenic DUOX1 and DUOX2 Mutations in Cases With Congenital Hypothyroidism.
- Author
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Aycan Z, Cangul H, Muzza M, Bas VN, Fugazzola L, Chatterjee VK, Persani L, and Schoenmakers N
- Subjects
- Codon, Nonsense, Cohort Studies, Dual Oxidases, Female, Genetic Variation, Genotype, Humans, Infant, Infant, Newborn, Male, NADPH Oxidases metabolism, Pedigree, Phenotype, Retrospective Studies, Severity of Illness Index, Thyroid Function Tests, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism genetics, Genetic Predisposition to Disease, NADPH Oxidases genetics
- Abstract
Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the thyroid peroxidase-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic congenital hypothyroidism (CH) that may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (e.g., dietary iodine) and oligogenic modifiers (e.g., variants in the homologous reduced form of NAD phosphate-oxidase DUOX1). However, loss-of-function mutations in DUOX1 have not hitherto been described, and its role in thyroid biology remains undefined., Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: thyrotropin >100 µU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (c.1823-1G>C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred., Conclusion: This is a report of digenic mutations in DUOX1 and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically ascertained CH., (Copyright © 2017 Endocrine Society)
- Published
- 2017
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23. Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland.
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Nicholas AK, Jaleel S, Lyons G, Schoenmakers E, Dattani MT, Crowne E, Bernhard B, Kirk J, Roche EF, Chatterjee VK, and Schoenmakers N
- Subjects
- Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism pathology, Delayed Diagnosis adverse effects, Female, Heterozygote, Homozygote, Humans, Hypothyroidism diagnosis, Hypothyroidism genetics, Hypothyroidism pathology, Infant, Newborn, Ireland, Male, Pedigree, Sequence Analysis, DNA, United Kingdom, Congenital Hypothyroidism genetics, Neonatal Screening methods, Thyrotropin, beta Subunit genetics
- Abstract
Objective: Homozygous mutations in the TSH beta subunit gene (TSHB) result in severe, isolated, central congenital hypothyroidism (CCH). This entity evades diagnosis in TSH-based congenital hypothyroidism (CH) screening programmes in the UK and Ireland. Accordingly, genetic diagnosis, enabling ascertainment of affected relatives in families, is critical for prompt diagnosis and treatment of the disorder., Design, Patients and Measurements: Four cases of isolated TSH deficiency from three unrelated families in the UK and Ireland were investigated for mutations or deletions in TSHB. Haplotype analysis, to investigate a founder effect, was undertaken in cases with identical mutations (c.373delT)., Results: Two siblings in kindred 1 were homozygous for a previously described TSHB mutation (c.373delT). In kindreds 2 and 3, the affected individuals were compound heterozygous for TSHB c.373delT and either a 5·4-kB TSHB deletion (kindred 2, c.1-4389_417*195delinsCTCA) or a novel TSHB missense mutation (kindred 3, c.2T>C, p.Met1?). Neurodevelopmental retardation, following delayed diagnosis and treatment, was present in 3 cases. In contrast, the younger sibling in kindred 1 developed normally following genetic diagnosis and treatment from birth., Conclusions: This study, including the identification of a second, novel, TSHB deletion, expands the molecular spectrum of TSHB defects and suggests that allele loss may be a commoner basis for TSH deficiency than previously suspected. Delayed diagnosis and treatment of profound central hypothyroidism in such cases result in neurodevelopmental retardation. Inclusion of thyroxine (T4) plus thyroxine-binding globulin (TBG), or free thyroxine (FT4) in CH screening, together with genetic case ascertainment enabling earlier therapeutic intervention, could prevent such adverse sequelae., (© 2016 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)
- Published
- 2017
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24. Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.
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Nicholas AK, Serra EG, Cangul H, Alyaarubi S, Ullah I, Schoenmakers E, Deeb A, Habeb AM, Almaghamsi M, Peters C, Nathwani N, Aycan Z, Saglam H, Bober E, Dattani M, Shenoy S, Murray PG, Babiker A, Willemsen R, Thankamony A, Lyons G, Irwin R, Padidela R, Tharian K, Davies JH, Puthi V, Park SM, Massoud AF, Gregory JW, Albanese A, Pease-Gevers E, Martin H, Brugger K, Maher ER, Chatterjee VK, Anderson CA, and Schoenmakers N
- Subjects
- Humans, Mutation, Pedigree, Phenotype, Autoantigens genetics, Congenital Hypothyroidism genetics, Iodide Peroxidase genetics, Iron-Binding Proteins genetics, Receptors, Thyrotropin genetics, Thyroglobulin genetics
- Abstract
Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken., Objective: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico., Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico., Results: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases., Conclusions: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
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- 2016
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25. The Hypercoagulable state in Hyperthyroidism is mediated via the Thyroid Hormone β Receptor pathway.
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Elbers LP, Moran C, Gerdes VE, van Zaane B, Meijers J, Endert E, Lyons G, Chatterjee VK, Bisschop PH, and Fliers E
- Abstract
Objective: Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor β (TRβ) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in TRβ-expressing tissues. We tested the hypothesis that the hypercoagulable state in hyperthyroidism is mediated via the TRβ., Design: We conducted a cross-sectional study from November 2013 to January 2015 in 3 hospitals in the Netherlands and the United Kingdom., Methods: Patients with RTH due to defective TRβ (n=18), patients with hyperthyroidism (n=16) and euthyroid subjects (n=18) were included. TH concentrations and markers of coagulation and fibrinolysis were measured. Data are expressed as median [interquartile range]., Results: Free thyroxine (FT4) levels were slightly higher in hyperthyroid patients than in RTH patients (53.9 [30.5-70.0] and 34.9 [28.4-42.2]pmol/l, respectively, P=0.042). Both groups had raised FT4 levels compared to euthyroid subjects (14.0 [13.0-15.8] pmol/l, P≤0.001). Levels of von Willebrand factor (VWF), factor (F) VIII, fibrinogen, and D-dimer were significantly higher in hyperthyroid patients than in RTH patients (VWF 231 [195-296] vs. 111 [82-140]%, FVIII 215 [192-228] vs. 145 [97-158]%, fibrinogen 3.6 [3.0-4.4] vs. 2.8 [2.5-3.2]g/L, D-dimer 0.41 [0.31-0.88] vs. 0.20 [0.17-0.26]mg/L, respectively, P≤0.001), while there were no differences between RTH patients and euthyroid controls., Conclusions: Parameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared to patients with RTH due to defective TRβ, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4 concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via the TRβ.
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- 2016
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26. Recent advances in central congenital hypothyroidism.
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Schoenmakers N, Alatzoglou KS, Chatterjee VK, and Dattani MT
- Subjects
- Congenital Hypothyroidism etiology, Humans, Infant, Newborn, Congenital Hypothyroidism diagnosis, Congenital Hypothyroidism physiopathology, Pituitary Gland physiopathology, Pituitary Hormones physiology
- Abstract
Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed., (© 2015 The authors.)
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- 2015
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27. Thyroid gland: TSHR mutations and subclinical congenital hypothyroidism.
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Schoenmakers N and Chatterjee VK
- Subjects
- Female, Humans, Male, Congenital Hypothyroidism genetics, Hypothyroidism genetics, Mutation, Receptors, Thyrotropin genetics
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- 2015
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28. An approach to quantifying abnormalities in energy expenditure and lean mass in metabolic disease.
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Watson LP, Raymond-Barker P, Moran C, Schoenmakers N, Mitchell C, Bluck L, Chatterjee VK, Savage DB, and Murgatroyd PR
- Subjects
- Adolescent, Adult, Female, Humans, Linear Models, Lipodystrophy physiopathology, Male, Middle Aged, Sex Factors, Thyroid Hormone Resistance Syndrome physiopathology, Thyrotoxicosis physiopathology, Body Composition, Energy Metabolism, Metabolic Diseases physiopathology
- Abstract
Background/objectives: The objective of this study was to develop approaches to expressing resting energy expenditure (REE) and lean body mass (LM) phenotypes of metabolic disorders in terms of Z-scores relative to their predicted healthy values., Subjects/methods: Body composition and REE were measured in 135 healthy participants. Prediction equations for LM and REE were obtained from linear regression and the range of normality by the standard deviation of residuals. Application is demonstrated in patients from three metabolic disorder groups (lipodystrophy, n=7; thyrotoxicosis, n=16; and resistance to thyroid hormone (RTH), n=46) in which altered REE and/or LM were characterised by departure from the predicted healthy values, expressed as a Z-score., Results: REE (kJ/min) = -0.010 × age (years)+0.016 × FM (kg)+0.054 × fat-free mass (kg)+1.736 (R2 = 0.732, RSD = 0.36 kJ/min). LM (kg)=5.30 × bone mineral content (kg)+10.66 × height2 (m)+6.40 (male). LM (kg)=0.20 × fat (kg)+14.08 × height2 (m)-2.93 (female).(male R2=0.55, RSD = 3.90 kg; female R2 = 0.59, RSD=3.85 kg).We found average Z-scores for REE and LM of 1.77 kJ/min and -0.17 kg in the RTH group, 5.82 kJ/min and -1.23 kg in the thyrotoxic group and 2.97 kJ/min and 4.20 kg in the LD group., Conclusion: This approach enables comparison of data from individuals with metabolic disorders with those of healthy individuals, describing their departure from the healthy mean by a Z-score.
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- 2014
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29. Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community.
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Cangul H, Aycan Z, Olivera-Nappa A, Saglam H, Schoenmakers NA, Boelaert K, Cetinkaya S, Tarim O, Bober E, Darendeliler F, Bas V, Demir K, Aydin BK, Kendall M, Cole T, Högler W, Chatterjee VK, Barrett TG, and Maher ER
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Pakistan, Thyroid Hormones biosynthesis, Thyroid Hormones genetics, Turkey, Congenital Hypothyroidism genetics, Consanguinity, Iodide Peroxidase genetics
- Abstract
Objective: In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH)., Context: Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease., Design: As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families., Patients: One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families., Measurements: Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out., Results: TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N)., Conclusions: This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases., (© 2012 John Wiley & Sons Ltd.)
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- 2013
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30. Quality of life in European patients with Addison's disease: validity of the disease-specific questionnaire AddiQoL.
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Øksnes M, Bensing S, Hulting AL, Kämpe O, Hackemann A, Meyer G, Badenhoop K, Betterle C, Parolo A, Giordano R, Falorni A, Papierska L, Jeske W, Kasperlik-Zaluska AA, Chatterjee VK, Husebye ES, and Løvås K
- Subjects
- Addison Disease diagnosis, Addison Disease physiopathology, Adolescent, Adult, Aged, Europe, Female, Germany epidemiology, Humans, Italy epidemiology, Male, Middle Aged, Norway epidemiology, Poland epidemiology, Reproducibility of Results, Sweden epidemiology, Young Adult, Addison Disease epidemiology, Addison Disease psychology, Quality of Life, Surveys and Questionnaires
- Abstract
Context: Patients with Addison's disease (AD) self-report impairment in specific dimensions on well-being questionnaires. An AD-specific quality-of-life questionnaire (AddiQoL) was developed to aid evaluation of patients., Objective: We aimed to translate and determine construct validity, reliability, and concurrent validity of the AddiQoL questionnaire., Methods: After translation, the final versions were tested in AD patients from Norway (n = 107), Sweden (n = 101), Italy (n = 165), Germany (n = 200), and Poland (n = 50). Construct validity was examined by exploratory factor analysis and Rasch analysis, aiming at unidimensionality and fit to the Rasch model. Reliability was determined by Cronbach's coefficient-α and Person separation index. Longitudinal reliability was tested by differential item functioning in stable patient subgroups. Concurrent validity was examined in Norwegian (n = 101) and Swedish (n = 107) patients., Results: Exploratory factor analysis and Rasch analysis identified six items with poor psychometric properties. The 30 remaining items fitted the Rasch model and proved unidimensional, supported by appropriate item and person fit residuals and a nonsignificant χ(2) probability. Crohnbach's α-coefficient 0.93 and Person separation index 0.86 indicate high reliability. Longitudinal reliability was excellent. Correlation with Short Form-36 and Psychological General Well-Being Index scores was high. A shorter subscale comprising eight items also proved valid and reliable. Testing of AddiQoL-30 in this large patient cohort showed significantly worse scores with increasing age and in women compared with men but no difference between patients with isolated AD and those with concomitant diseases., Conclusion: The validation process resulted in a revised 30-item AddiQoL questionnaire and an eight-item AddiQoL short version with good psychometric properties and high reliability.
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- 2012
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31. What should be done when thyroid function tests do not make sense?
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Gurnell M, Halsall DJ, and Chatterjee VK
- Subjects
- Diagnosis, Differential, Humans, Reproducibility of Results, Sensitivity and Specificity, Thyroid Function Tests methods, Thyrotropin blood, Thyroxine blood, Triiodothyronine blood, Algorithms, Hyperthyroxinemia blood, Hyperthyroxinemia diagnosis, Thyroid Function Tests standards
- Abstract
Interpretation of thyroid function tests (TFTs) is generally straightforward. However, in a minority of contexts the results of thyroid hormone and thyrotropin measurements either conflict with the clinical picture or form an unusual pattern. In many such cases, reassessment of the clinical context provides an explanation for the discrepant TFTs; in other instances, interference in one or other laboratory assays can be shown to account for divergent results; uncommonly, genetic defects in the hypothalamic-pituitary-thyroid axis are associated with anomalous TFTs. Failure to recognize these potential 'pitfalls' can lead to misdiagnosis and inappropriate management. Here, focusing particularly on the combination of hyperthyroxinaemia with nonsuppressed thyrotropin, we show how a structured approach to investigation can help make sense of atypical TFTs., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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32. Maternal isodisomy for chromosome 9 causing homozygosity for a novel FOXE1 mutation in syndromic congenital hypothyroidism.
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Castanet M, Mallya U, Agostini M, Schoenmakers E, Mitchell C, Demuth S, Raymond FL, Schwabe J, Gurnell M, and Chatterjee VK
- Subjects
- Adolescent, Cleft Palate genetics, Female, Genotype, Homozygote, Humans, Microsatellite Repeats, Mutation, Chromosomes, Human, Pair 9 genetics, Congenital Hypothyroidism genetics, Forkhead Transcription Factors genetics, Uniparental Disomy genetics
- Abstract
Context: Homozygous loss-of-function mutations in forkhead box E1/thyroid transcription factor 2 (FOXE1/TTF-2) cause syndromic congenital hypothyroidism, with thyroid dysgenesis, cleft palate, spiky hair, and variable choanal atresia and bifid epiglottis in three cases reported hitherto. We have elucidated the molecular basis of the disorder in a female with a similar clinical phenotype, born to nonconsanguineous parents., Objective and Design: The FOXE1 gene, located on chromosome 9q22, was sequenced in the proband and family members. Microsatellite marker and multiplex ligation probe amplification analyses determined chromosomal inheritance patterns and FOXE1 copy number. Mutant FOXE1 function was predicted by structural modeling and tested in transfection assays., Results: The proband was homozygous for a novel missense (c.412T-->C; F137S) FOXE1 mutation, but her mother showed heterozygous and father wild-type alleles for this gene sequence. However, the proband was also homozygous for 10 microsatellite markers spanning chromosome 9 with exclusively maternal inheritance. Multiplex ligation probe amplification assays showed two copies of FOXE1 in the proband, indicating maternal isodisomy for chromosome 9. Consistent with structural modeling, the F137S mutant FOXE1 protein failed to bind DNA and showed negligible transcriptional activity., Conclusion: We have described the first case of uniparental disomy causing homozygosity for a novel, loss-of-function FOXE1/TTF-2 mutation in dysgenetic congenital hypothyroidism.
- Published
- 2010
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33. Immunoglobulin interference in serum follicle-stimulating hormone assays: autoimmune and heterophilic antibody interference.
- Author
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Webster R, Fahie-Wilson M, Barker P, Chatterjee VK, and Halsall DJ
- Subjects
- Adolescent, False Positive Reactions, Female, Follicle Stimulating Hormone immunology, Humans, Male, Young Adult, Antibodies, Heterophile immunology, Artifacts, Autoimmunity immunology, Blood Chemical Analysis methods, Follicle Stimulating Hormone blood, Immunoassay methods
- Abstract
Interference in immunoassay caused by endogenous immunoglobulin is a cause of incorrect laboratory results that can drastically affect patient management. Two cases of immunoglobulin interference in serum follicle-stimulating hormone (FSH) assays are presented. These cases illustrate two common mechanisms for false-positive interference in two-site (sandwich) immunoassays. The first case describes a circulating autoimmune FSH immunoglobulin complex ('macro'-FSH), which has not been previously described for FSH, and the second a cross-linking antibody directed against the assay reagents. Immunoglobulin interference was detected and characterized using a combination of method comparison, immunosubtraction and size exclusion chromatography.
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- 2010
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34. Development of a disease-specific quality of life questionnaire in Addison's disease.
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Løvås K, Curran S, Oksnes M, Husebye ES, Huppert FA, and Chatterjee VK
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Addison Disease psychology, Quality of Life, Surveys and Questionnaires
- Abstract
Context: Patients with Addison's disease reproducibly self-report impairment in specific dimensions of general well-being questionnaires, suggesting particular deficiencies in health-related quality-of-life (HRQoL)., Objective: We sought to develop an Addison's disease-specific questionnaire (AddiQoL) that could better quantify altered well-being and treatment effects. Design, Setting, Patients, Intervention, and Outcomes: We reviewed the literature to identify HRQoL issues in Addison's disease and interviewed patients and their partners in-depth to explore various symptom domains. A list of items was generated, and nine expert clinicians and five expert patients assessed the list for impact and clarity. A preliminary questionnaire was presented to 100 Addison's outpatients; the number of items was reduced after analysis of the distribution of the responses. The final questionnaire responses were assessed by Cronbach's alpha and Rasch analysis., Results and Interpretation: Published studies of HRQoL in Addison's disease indicated reduced vitality and general health perception and limitations in physical and emotional functioning. In-depth interviews of 14 patients and seven partners emphasized the impact of the disease on the emotional domain. Seventy HRQoL items were generated; after the expert consultation process and pretesting in 100 patients, the number of items was reduced to 36. Eighty-six patients completed the final questionnaire; the responses showed high internal consistency with Cronbach's alpha 0.95 and Person Separation Index 0.94 (Rasch analysis)., Conclusions: We envisage AddiQoL having utility in trials of hormone replacement and management of patients with Addison's disease, analogous to similar questionnaires in GH deficiency (AGHDA) and acromegaly (AcroQoL).
- Published
- 2010
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35. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC.
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Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, Vigouroux C, Magré J, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O'Rahilly S, and Savage DB
- Subjects
- 3T3 Cells, Animals, Apoptosis Regulatory Proteins, Base Sequence, Diabetes Mellitus metabolism, Female, Humans, Lipodystrophy metabolism, Male, Mice, Molecular Sequence Data, Pedigree, Protein Transport, Proteins metabolism, Young Adult, Codon, Nonsense, Diabetes Mellitus genetics, Insulin Resistance, Lipodystrophy genetics, Proteins genetics
- Abstract
Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
- Published
- 2009
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36. Interference from heterophilic antibodies in TSH assays.
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Halsall DJ, English E, and Chatterjee VK
- Subjects
- Humans, Antibodies, Heterophile immunology, Biological Assay methods, Immunoassay methods, Thyrotropin immunology
- Published
- 2009
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37. Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone.
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Løvås K, Gjesdal CG, Christensen M, Wolff AB, Almås B, Svartberg J, Fougner KJ, Syversen U, Bollerslev J, Falch JA, Hunt PJ, Chatterjee VK, and Husebye ES
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Adolescent, Adult, Aged, Bone Density, Cohort Studies, Cross-Sectional Studies, Female, Humans, Hydrocortisone therapeutic use, Male, Middle Aged, New Zealand, Polymorphism, Genetic genetics, Polymorphism, Genetic physiology, United Kingdom, Young Adult, Addison Disease drug therapy, Addison Disease genetics, Bone and Bones metabolism, Glucocorticoids therapeutic use, Hormone Replacement Therapy methods, Pharmacogenetics
- Abstract
Unlabelled: Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone., Objective: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics., Design, Setting and Participants: A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105)., Main Outcome Measures: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity., Results: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine., Conclusions: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.
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- 2009
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38. Familial dysalbuminemic hyperthyroxinemia: a persistent diagnostic challenge.
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Cartwright D, O'Shea P, Rajanayagam O, Agostini M, Barker P, Moran C, Macchia E, Pinchera A, John R, Agha A, Ross HA, Chatterjee VK, and Halsall DJ
- Subjects
- Humans, Reagent Kits, Diagnostic, Hyperthyroxinemia, Familial Dysalbuminemic blood, Thyroxine blood
- Published
- 2009
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39. Augmentation index in resistance to thyroid hormone (RTH).
- Author
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Owen PJ, Chatterjee VK, John R, Halsall D, and Lazarus JH
- Subjects
- Adult, Blood Glucose metabolism, Cardiovascular Diseases epidemiology, Case-Control Studies, Cholesterol, LDL blood, Cohort Studies, Female, Humans, Male, Middle Aged, Risk Factors, Thyroid Gland physiopathology, Thyroid Hormone Resistance Syndrome blood, Thyroid Hormone Resistance Syndrome complications, Thyrotropin blood, Thyroxine blood, Triiodothyronine blood, Elasticity physiology, Pulsatile Flow physiology, Radial Artery physiopathology, Thyroid Hormone Resistance Syndrome physiopathology
- Abstract
Objective: Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes., Design: An observational study., Patients: Twelve RTH patients were recruited from the thyroid clinic (mean value +/- SD), age 40.8 +/- 18.7 years; BMI 27.2 +/- 4.2 kg/m(2) and compared with 12 healthy, euthyroid, age-matched controls (age 41.4 +/- 19.3; BMI 24.8 +/- 4.4 kg/m(2)) with no history of cardiovascular disease. No interventional measures were instituted., Measurements: Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls. Results The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21.0% +/- 14.1%vs. 5.4% +/- 18.2%, P < 0.03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3.0 +/- 0.6 vs. 2.1 +/- 0.5 mmol/l; P < 0.002)., Conclusion: RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.
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- 2009
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40. A novel CYP11B2 gene mutation in an Asian family with aldosterone synthase deficiency.
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Løvås K, McFarlane I, Nguyen HH, Curran S, Schwabe J, Halsall D, Bernhardt R, Wallace AM, and Chatterjee VK
- Subjects
- Adult, Aldosterone blood, Humans, Male, Cytochrome P-450 CYP11B2 deficiency, Cytochrome P-450 CYP11B2 genetics, Mutation
- Abstract
Context: Three siblings of Pakistani origin presented neonatally with isolated hyperreninemic hypoaldosteronism and were well controlled on fludrocortisone therapy during childhood and adolescence., Objective/design: These individuals were reevaluated as adults after fludrocortisone withdrawal to investigate the biochemical and molecular basis of their disorder., Results: When reassessed off fludrocortisone treatment, hyperreninemic hypoaldosteronism was confirmed in all subjects but with significant hyperkalemia in only one case. Profiling of urinary steroid metabolites showed a biochemical pattern (elevated tetrahydrocorticosterone to 18-hydroxytetrahydro-11-dehydrocorticosterone ratio but normal 18-hydroxytetrahydro-11-dehydrocorticosterone to tetrahydroaldosterone ratio) consistent with partial type 1 aldosterone synthase deficiency. Sequencing of the CYP11B2 gene showed that affected subjects were homozygous for a single nucleotide substitution (T925C) in exon 5, corresponding to a serine to proline mutation (S308P) in the predicted protein, with unaffected family members being heterozygous. Consistent with structural modeling showing that the mutated residue is located within the alpha-helix I, close to the hemebinding, active site of the enzyme, functional characterization of the S308P mutant protein in vitro showed complete loss of enzyme activity. However, administration of dexamethasone further reduced levels of circulating aldosterone and its urinary metabolites in affected subjects, suggesting that some mineralocorticoid biosynthesis occurs in vivo., Conclusion: We have identified the first CYP11B2 gene defect in a family of Asian origin, associated with a type 1 aldosterone synthase deficiency phenotype. Preservation of some aldosterone production suggests either residual mutant CYP11B2 enzyme activity in vivo or mineralocorticoid biosynthesis via an alternative pathway.
- Published
- 2009
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41. Nuclear receptors and human disease: resistance to thyroid hormone and lipodystrophic insulin resistance.
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Chatterjee VK
- Subjects
- Animals, Humans, PPAR gamma metabolism, Thyroid Hormone Resistance Syndrome physiopathology, Dyslipidemias metabolism, Insulin Resistance physiology, Receptors, Cytoplasmic and Nuclear metabolism, Thyroid Hormones physiology
- Published
- 2008
- Full Text
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42. Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial.
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Gurnell EM, Hunt PJ, Curran SE, Conway CL, Pullenayegum EM, Huppert FA, Compston JE, Herbert J, and Chatterjee VK
- Subjects
- Absorptiometry, Photon, Addison Disease blood, Adult, Aged, Body Composition drug effects, Bone Density drug effects, Cognition drug effects, Dehydroepiandrosterone Sulfate blood, Double-Blind Method, Female, Humans, Male, Middle Aged, Prospective Studies, Quality of Life, Statistics, Nonparametric, Surveys and Questionnaires, Addison Disease drug therapy, Dehydroepiandrosterone therapeutic use, Hormone Replacement Therapy methods
- Abstract
Context: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison's disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected., Objective and Design: In a double-blind trial, we randomized 106 subjects (44 males, 62 females) with Addison's disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue., Results: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (P < 0.05) but not at other sites; DHEA enhanced total body (P = 0.02) and truncal (P = 0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (Short Form-36, General Health Questionnaire-30), were significantly worse in Addison's patients vs. control populations (P < 0.001), and one subscale of SF-36 improved significantly (P = 0.004) after DHEA treatment. There was no significant benefit of DHEA treatment on fatigue or cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects., Conclusion: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison's disease.
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- 2008
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43. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.
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Manji N, Carr-Smith JD, Boelaert K, Allahabadia A, Armitage M, Chatterjee VK, Lazarus JH, Pearce SH, Vaidya B, Gough SC, and Franklyn JA
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- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Cohort Studies, Female, Goiter complications, Goiter epidemiology, Graves Disease epidemiology, Graves Disease etiology, Graves Disease genetics, Graves Ophthalmopathy epidemiology, Graves Ophthalmopathy etiology, Hashimoto Disease epidemiology, Hashimoto Disease genetics, Humans, Male, Middle Aged, Phenotype, Sex Factors, Genetic Predisposition to Disease, Hashimoto Disease diagnosis, Smoking adverse effects
- Abstract
Context: Both genetic and environmental factors contribute to susceptibility to Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as disease manifestations., Objective: The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype., Design/setting: This was a multicenter cohort study. PATIENTS/OUTCOME MEASURES: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations., Results: For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T4 at diagnosis) (P < 0.001). Free T4 (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01)., Conclusions: Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.
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- 2006
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44. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors.
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Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, Palmer CN, Plutzky J, Reddy JK, Spiegelman BM, Staels B, and Wahli W
- Subjects
- Animals, Binding Sites, Humans, Hypoglycemic Agents pharmacology, Ligands, Mutation, Peroxisome Proliferator-Activated Receptors agonists, Peroxisome Proliferator-Activated Receptors genetics, Pioglitazone, Protein Isoforms agonists, Protein Isoforms genetics, Protein Isoforms metabolism, Thiazolidinediones pharmacology, Fatty Acids, Unsaturated metabolism, Peroxisome Proliferator-Activated Receptors metabolism
- Abstract
The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARalpha is expressed at high levels in organs with significant catabolism of fatty acids. PPARbeta/delta has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARgamma is expressed as two isoforms, of which PPARgamma2 is found at high levels in the adipose tissues, whereas PPARgamma1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARalpha and PPARgamma agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.
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- 2006
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45. Macro thyrotropin-IgG complex causes factitious increases in thyroid-stimulating hormone screening tests in a neonate and mother.
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Halsall DJ, Fahie-Wilson MN, Hall SK, Barker P, Anderson J, Gama R, and Chatterjee VK
- Subjects
- Chromatography, Gel, Congenital Hypothyroidism diagnosis, False Positive Reactions, Female, Humans, Immunoglobulin G metabolism, Infant, Newborn, Neonatal Screening, Thyroid Function Tests, Thyrotropin metabolism, Antigen-Antibody Complex blood, Immunoglobulin G blood, Thyrotropin blood
- Published
- 2006
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46. Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor gamma function (P465L PPARgamma) in mice.
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Gray SL, Nora ED, Grosse J, Manieri M, Stoeger T, Medina-Gomez G, Burling K, Wattler S, Russ A, Yeo GS, Chatterjee VK, O'Rahilly S, Voshol PJ, Cinti S, and Vidal-Puig A
- Subjects
- Adipose Tissue pathology, Animals, Blood Glucose metabolism, Gene Expression Profiling, Genes, Lethal, Homozygote, Insulin blood, Insulin Resistance genetics, Leptin genetics, Lipid Metabolism genetics, Mice, Mice, Obese, PPAR gamma genetics, Leptin deficiency, PPAR gamma physiology
- Abstract
Peroxisome proliferator-activated receptor (PPAR)gamma is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARgamma display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPARgamma developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPARgamma-related findings, bringing into question the relevance of other PPARgamma murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPARgamma mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPARgamma mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPARgamma mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPARgamma mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance.
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- 2006
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47. A novel missense mutation in human TTF-2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis.
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Baris I, Arisoy AE, Smith A, Agostini M, Mitchell CS, Park SM, Halefoglu AM, Zengin E, Chatterjee VK, and Battaloglu E
- Subjects
- Amino Acid Sequence, Female, Humans, Infant, Newborn, Molecular Sequence Data, Forkhead Transcription Factors genetics, Hypothyroidism genetics, Mutation, Missense, Thyroid Gland abnormalities
- Abstract
Background: Thyroid dysgenesis is the most frequent cause of congenital hypothyroidism (CH), and its genetic basis is largely unknown. Hitherto, two mutations in the human thyroid transcription factor 2 (TTF-2) gene have been described in unrelated cases of CH with cleft palate, spiky hair, variable choanal atresia, and complete thyroid agenesis. Here, we describe a novel TTF-2 mutation in a female child resulting in syndromic CH in the absence of thyroid agenesis., Results: The index case is homozygous for an arginine to cysteine mutation (R102C) of a highly conserved residue within the forkhead, DNA binding domain of TTF-2. Her consanguineous, heterozygous parents are unaffected, and the mutation was not detected in 100 control chromosomes. Consonant with its location, the R102C mutant TTF-2 protein showed loss of DNA binding and was transcriptionally inactive. CH in the proposita was associated with cleft palate, spiky hair, and bilateral choanal atresia. However, radiological studies showed the presence of thyroid tissue in a eutopic location., Conclusion: Our findings indicate that human thyroid development can occur despite loss of TTF-2 function and suggest that TTF-2 gene defects should also be considered in cases of syndromic CH without total athyreosis.
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- 2006
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- View/download PDF
48. Elevated plasma adiponectin in humans with genetically defective insulin receptors.
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Semple RK, Soos MA, Luan J, Mitchell CS, Wilson JC, Gurnell M, Cochran EK, Gorden P, Chatterjee VK, Wareham NJ, and O'Rahilly S
- Subjects
- Adolescent, Adult, Body Mass Index, Child, Child, Preschool, Fasting, Female, Humans, Infant, Infant, Newborn, Insulin blood, Leptin blood, Male, Syndrome, Adiponectin blood, Insulin Resistance genetics, Mutation, Receptor, Insulin genetics
- Abstract
Context: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity., Objective: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance., Design/setting: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States., Participants: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls., Outcome Measures: Fasting plasma insulin, adiponectin, and leptin were measured., Results: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6-36.6 (normal adult range for body mass index 20 kg/m(2) = 3-19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0-16: normal adult range for body mass index of < 25 kg/m(2) = 2.4-24.4 (female) and 0.4-8.3 ng/ml (male)]., Conclusions: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.
- Published
- 2006
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49. Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone.
- Author
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Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, and Eng C
- Subjects
- Cell Line, Tumor, Dose-Response Relationship, Drug, G1 Phase drug effects, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, PPAR gamma physiology, Rosiglitazone, Transcriptional Activation, Up-Regulation, Antineoplastic Agents pharmacology, Breast Neoplasms pathology, Hypoglycemic Agents pharmacology, Lovastatin pharmacology, PTEN Phosphohydrolase biosynthesis, Thiazolidinediones pharmacology
- Abstract
Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease., (Copyright (c) 2006 Wiley-Liss, Inc.)
- Published
- 2006
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50. PPAR gamma and human metabolic disease.
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Semple RK, Chatterjee VK, and O'Rahilly S
- Subjects
- Humans, Metabolic Diseases genetics, PPAR gamma genetics, Metabolic Diseases physiopathology, PPAR gamma physiology
- Abstract
The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARalpha, PPARdelta, and PPARgamma) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARalpha and PPARdelta appear primarily to stimulate oxidative lipid metabolism, while PPARgamma is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARgamma in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARgamma in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.
- Published
- 2006
- Full Text
- View/download PDF
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