ETA2022 Oral Presentations Oral Session 8: Basic 2 (5 abstracts)
Resistance to thyroid hormone alpha: molecular, biochemical and physiological approach to diagnosis and therapy
Maura Agostini 1 , Maik Pietzner 2 , Federica Marelli 3 , Matina Prapa 4 , Carla Moran 5 , W. Edward Visser 6 , Dave Brown 7 , Ellen Thomas 7 , Erik Schoenmakers 8 , Beatriz Romartinez-Alonso 9 , Rabea Scheuplein 10 , Anna Tylki-Szymanska 11 , Greta Lyons 12 , Laura Watson 12 , Odelia Rajanayagam 13 , Edzard Schwedhelm 14 , Michaela F. Hartmann 15 , Stefan Wudy 16 , Maiken Probst 17 , Stephen MacDonald 18 , William Thomas 18 , Wiebke Arlt 19 , Uwe Völker 20 , Katharina M. Main 21 , Ulla Feldt-Rasmussen 22 , Mehul T. Dattani 23 , Louise Koren Dahll 24 , Korcan Demir 25 , Cengiz Kara 26 , Ozgur Kirbiyik 27 , Jamala Mammadova 28 , Atilla Çayır 29 , Oguzhan Yarali 30 , Franziska Phan-Hug 31 , Rajesh Sakremath 32 , Zainaba Mohamed 33 , Marwan Shinawi 34 , Harpreet Gill 35 , Daniele pacaud 36 , Renee Perrier 35 , Gemma Poke 37 , Wendy Hunter 38 , Sofia Douzgou 39 , Emma Wakeling 40 , Alice Gardham 41 , Derek Lim 42 , Deborah Shears 43 , Marie Freel 44 , Jasna Omladic 45 , Mojca Tansek 45 , Karin Writzl 46 , Sadaf Farooqi 47 , Peter Kopp 31 , John Schwabe 48 , Luca Persani 49 & Krishna Chatterjee 50
1Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; 2Berlin Institute of Health at Charite-Universitatsmedizin Berlin, Germany; 3Irccs Istituto Auxologico Italiano, Lab. of Endocrine and Metabolic Research, Lab of Endocrine and Metabolic Research, Cusano Milanino, Italy; 4Department of Clinical Genetics, Addenbrooke’s Hospital, Cambridge, United Kingdom; 5Endocrine Dept, Endocrine, Ucd School of Medicine, Dublin, Ireland; 6Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands; 7Genomics England, London, United Kingdom; 8Institute of Metabolic Science, Clinical Biochemistry, Cambridge, United Kingdom; 9Institute of Structural and Chemical Biology, Leicester, United Kingdom; 10Institut Fur Genetik und Funktionelle Genomforschung, Greifswald, Germany; 11The Children’s Memorial Health Institute, Warsaw, Poland; 12Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom; 13Institute of Metabolic Science, Cambridge, United Kingdom; 14Institute for Clinical Pharmacology and Toxicology, Hamburg, Germany; 15Steroid Research & Mass Spectrometry Unit, Center of Child and Adolescent Medicine, Justus-Liebig-University, Gießen, Germany; 16Steroid Research and Mass Spectrometry Unit, Center of Child and Adolescent Medicine, Justus-Liebig-University, Giessen, Germany, Gießen, Germany; 17Department of Growth and Reproduction, Righospitalet, Copenhagen, Denmark; 18Department of Haematology, Addenbrooke’s Hospital, Cambridge, United Kingdom; 19Institute of Metabolism and Systems Research, Institute of Metabolism and Systems Research (Imsr), University of Birmingham, University of Birmingham, Birmingham, United Kingdom; 20Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; 21Dept. of Growth and Reproduction, Rigshospitalet, University of Copenhangen, Copenhagen, Denmark; 22Department of Medical Endocrinology, Section 2132, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, Rigshospitalet, Endocrinology, Copenhagen, Denmark; 23Great Ormond Street Hospital for Children, London, United Kingdom; 24Hormone Laboratory, Oslo University Hospital, Oslo, Norway; 25Division of Pediatric Endocrinology, Dr. Behcet Uz Children’s Hospital, Izmir, Turkey; 26Ondokuzmayis University, Medical School, Department of Paediatric Endocrinology and Diabetes, Samsun, Turkey; 27Tepecik Training and Research Hospital, University of Health Sciences, Genetic Diagnosis Center, Izmir, Turkey; 28Ondokuz Mayis University, Department of Paediatric Endocrinology, Samsun, Turkey; 29Erzurum Regional Training and Research Hospital, Department of Pediatric Endocrinology, Erzurum, Turkey; 30Erzurum Regional Training and Research Hospital, Clinics of Medical Genetics, Erzurum, Turkey; 31University of Lausanne, Division of Endocrinology, Diabetes and Metabolism, Switzerland; 32Shrewsbury and Telford Hospital, United Kingdom; 33Birmingham Women’s and Children’s Hospital, Department of Paediatric Endocrinology, Birmingham, United Kingdom; 34Washington University School of Medicine, Saint Louis, United States; 35Alberta Children’s Hospital, Department of Pediatrics, Calgary, Canada; 36Alberta Children’s Hospital, University of Calgary, Calgary, Canada; 37Genetic Health Service Nz, Wellington Hospital, New Zealand; 38Nelson Marlborough District Health Board, Department of Pediatrics, Nelson, New Zealand; 39St Mary’s Hospital, Department of Clinical Genetics, Manchester, United Kingdom; 40Great Ormond Street Hospital, Department of Clinical Genetics, London, United Kingdom; 41North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, United Kingdom; 42Birmingham Women’s and Children’s Hospital, Clinical Genetics Unit, Birmingham, United Kingdom; 43Oxford Centre for Genomic Medicine, Oxford, United Kingdom; 44Queen Elizabeth University Hospital, Department of Endocrinology, Glasgow, United Kingdom; 45Children’s Hospital, Department of Pediatrics, Ljubjana, Slovenia; 46University Medical Center, Institute of Genomic Medicine, Ljubjana, Slovenia; 47University of Cambridge, Level 4, Institute of Metabolic Science, Cambridge, United Kingdom; 48Henry Wellcome Laboratories of Structural Biology, University of Leicester, Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom; 49University of Milan, Irccs Istituto Auxologico Italiano, Ospedale San Luca, Milan, Italy; 50University of Cambridge, Wellcome-Mrc Institute of Metabolic Science, Cambridge, United Kingdom
Objectives: THRA mutations cause Resistance to Thyroid Hormone α (RTHα), an underdiagnosed disorder with hypothyroid features but near-normal thyroid function tests (TFTs). We developed a pathway, combining molecular analyses, new biomarkers and physiological measurements, to better diagnose and treat this disorder.
Methods: Structural and functional analyses of THRA variants, discovered by next generation sequencing in specific projects (eg 100K Genome, Deciphering Developmental Delay, Genetics of Obesity study) or unbiased investigation of patients, identified an RTHα cohort (n=32). In this cohort, we measured plasma metabolites or proteins and analysed facial images using artificial intelligence (AI) to differentiate RTHα from controls. We measured resting energy expenditure (REE) during thyroxine therapy of the disorder.
Results: 17 different, heterozygous THRA variants, in individuals investigated for diverse causes (growth retardation, developmental delay, autism, dysmorphic facies) localised to the hormone binding domain of TRα1, with 14 being homologous to THRB mutations causing RTHβ. Varying transcriptional impairment or morphological and skeletal abnormalities when variants were expressed in mammalian cells or developing zebrafish and reduced KLF9 expression in variant-containing, patients’ blood cells, led to their classification as pathogenic. 12 novel TRα mutations (R228C, R266L, D268N, Δ268-272, T275M, G278R, V282L, L287P, I299T, H381Q, P399S, L400Tfs*7) were identified. Mutations occurred de novo in 20/32 patients, including at a mutation hotspot (G291S) in five, unrelated, cases. With TFTs being near-normal (concentrations in reference range: TSH 100%; FT4 85%; RT3 70%; FT3 50%) in patients, ‘omics technologies identified plasma metabolites or proteins, whose relative levels distinguish RTHα cases from controls with 95% accuracy. Validating this, plasma concentrations of the most important metabolites and protein differed significantly (RTHα vs Controls: Assymetric dimethylamine, (P=3.7E-05), pregnenolone sulphate (P=1.98E-07), or Factor XIII (P=1.1E-11). AI-guided scores of facial features in RTHα cases and controls differed significantly, generating a classifier with a receiver operating characteristic of 0.966. Thyroxine therapy, in TSH-suppressive dosage, raised REE from low (Z scores -3.58 to -0.02) to higher levels.
Conclusions: In silico analyses of THRA variants of unknown significance, identifies TRα mutations whose loss-of-function is confirmed using transcriptional, zebrafish model and patient cell-based assays. New biomarker and AI-guided dysmorphic feature analyses in individuals with mutant genotypes diagnoses RTHα, enabling thyroxine therapy to correct subnormal energy expenditure.
Volume 84
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Endocrine Abstracts
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