Searchable abstracts of presentations at key conferences in endocrinology

ea0092op-07-01 | Oral Session 7: Thyroid hormone receptors | ETA2023

Monocyte and macrophage function is impaired in patients with resistance to thyroid hormone due to a mutation in thyroid hormone receptor ALPHA

van der Spek Anne , Agostini Maura , Boelen Anita , Chatterjee Krishna

Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha (RTHα) is a syndrome whose features include delayed growth and neurocognitive development. Macrophages, which derive from circulating monocytes and have recently been recognized as important thyroid hormone target cells, are innate immune cells that are capable of adopting a wide range of phenotypes. Assuming the right phenotype in the right setting is crucial as macrophage dysfunction has b...

ea0092op-07-03 | Oral Session 7: Thyroid hormone receptors | ETA2023

Rapid screening of thra variants pathogenicity in the zebrafish model

Marelli Federica , Agostini Maura , Moran Carla , Chatterjee Krishna , Persani Luca

Mutations in THRA, a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone α (RTHα). RTHα manifests with features of hypothyroidism (skeletal dysplasia and growth retardation, neurocognitive impairment, low metabolic rate, reduced intestinal transit) reflecting hormone resistance in TRα-expressing tissues, but associated paradoxically with near-normal circulating TH levels. The lack of clear-cut, abnormal thyroid function tests...

ea0028oc1.4 | Young Endocrinologists prize session | SFEBES2012

The thyroid hormone receptor-coactivator interface mediates negative feedback regulation of the human pituitary-thyroid axis

Moran Carla , Mitchell Catherine , Agostini Maura , Schoenmakers Erik , Gregory John , Gurnell Mark , Chatterjee Krishna

Corepressors and coactivators of thyroid hormone receptor-mediated function facilitate repression and transactivation of positively-regulated target genes respectively, but their role in negative regulation is not understood. A 13 yr old boy, born at 31 weeks gestation, was jittery at birth, with neonatal respiratory distress. Childhood features included poor weight gain, heat intolerance, tachycardia and hyperactivity. Ongoing problems are low frequency hearing loss, poor sig...

ea0015oc34 | Thyroid | SFEBES2008

Maternal isodisomy for a novel human FOXE1 gene mutation in syndromic congenital hypothyroidsim

Castanet Mireille , Mallya Uma , Agostini Maura , Mitchell Catherine , Polak Michel , Demuth Stephanie , Raymond Lucy , Gurnell Mark , Chatterjee Krishna

Congenital hypothyroidism (CH), occurs with a frequency of one in 3–4000 and is most commonly due (85%) to complete or partial failure of thyroid gland development (dysgenesis). Several transcription factors (TTF-1/Nkx2.1, TTF-2/FOXE1, PAX-8), are highly expressed in the developing rodent thyroid. We first showed that the FKHL15 gene is the human homologue of TTF-2, identifying a homozygous, loss-of-function, mutation in two siblings with CH, thyroid agenesis, clef...

ea0092ps2-20-05 | Thyroid hormone receptors basic | ETA2023

Human resistance to thyroid hormone beta operates via a mechanism requiring receptor binding to DNA

Agostini Maura , Schoenmakers Erik , acar sezer , Syanda Adam , Romartinez-Alonso Beatriz , Cacciottolo Tessa , Rashid Tamir , Schwabe John , Chatterjee Krishna

Objectives: All known (>230) different mutations in thyroid hormone receptor β (TRβ) causing Resistance to Thyroid Hormone β (RTHβ), localise to three clusters within its hormone binding domain. Here, we report phenotypes and molecular studies in an unique family with RTHβ due to a mutation in the DNA binding domain (DBD) of TRβ.Methods: We ascertained clinical and biochemical features in four children and their parents ...

ea0084ps2-09-84 | Thyroid Hormone ACTION | ETA2022

Molecular mechanisms underlying action of triac in resistance to thyroid hormone BETA (RTHβ)

Liao Wenjun , van Geest Ferdy , Marelli Federica , Campi Irene , Moran Carla , Lyons Greta , Agostini Maura , Peeters Robin , Chatterjee Krishna , Persani Luca , Meima Marcel , Edward Visser W.

Background: Resistance to thyroid hormone (TH) beta (RTHβ), caused by mutations in THRB, is characterized by elevated serum (F)T4 accompanied by non-suppressed TSH concentrations. Disease features arise from variable resistance to TH action in tissues expressing Thyroid Hormone Receptor (TR) β (hypothalamus, pituitary, liver) and from thyrotoxic effects in tissues expressing TRα (heart, bone, brain). In symptomatic patients, treatment mainly involves be...

ea0044p241 | Thyroid | SFEBES2016

Contrasting phenotypes in Resistance to Thyroid Hormone α correlate with divergent properties of thyroid hormone receptor α1 mutant proteins

Moran Carla , Agostini Maura , McGowan Anne , Schoenmakers Erik , Fairall Louise , Lyons Greta , Rajanayagam Odelia , Watson Laura , Offish Amaka , Barton John , Price Susan , Schwabe John , Chatterjee Krishna

Resistance to Thyroid Hormone alpha (RTHα) is characterised by tissue-selective hypothyroidism with near-normal thyroid function tests, and is due to thyroid receptor α gene mutations. We sought to correlate the clinical characteristics and response to thyroxine treatment of two RTHα patients with the properties of their defective TRα proteins.Clinical, biochemical and physiological parameters were assessed in each patient at baseline...

ea0059p154 | Obesity & metabolism | SFEBES2018

Dominant-negative mutations in PPAR alpha are present in unselected human populations and have a metabolic signature

Melvin Audrey , Lam Brian , Langenberg Claudia , Agostini Maura , Schoenmakers Erik , Luan Jian'an , Rainbow Kara , Yeo Giles S , Wareham Nick , Savage David B , Chatterjee Krishna , O'Rahilly Stephen

The study of humans carrying dominant negative mutations in PPAR gamma has contributed significantly to our understanding of its role in human physiology. To date, comparable studies of PPAR alpha have not been reported. Using a pooled approach, we undertook exon sequencing of PPARA in 11,848 adult participants of the Fenland study, a population-based cohort study with detailed metabolic phenotyping. Twenty-nine PPARA missense variants were detected (allelic ...

ea0015p152 | Diabetes, metabolism and cardiovascular | SFEBES2008

Weight gain, on the background of human PPARγ haploinsufficiency, exposes a metabolic phenotype

Mitchell Catherine , Al-Ali Nadia , Savage David , Simpson Helen , Luan Jian'an , Semple Robert , Agostini Maura , Wareham Nicholas , Gurnell Mark , O'Rahilly Stephen , Chatterjee V Krishna

Peroxisome proliferator activated receptor gamma (PPARγ), a ligand-inducible transcription factor, is essential for adipocyte differentiation and lipogenesis. We previously described a kindred in which some individuals were heterozygous for a frameshift/premature stop mutation, (A553ΔAAAiT)fs.185(stop186) in PPARγ, with the truncated protein being non-functional and lacking dominant negative activity1. PPARγ null heterozygotes had norm...

ea0084op-01-04 | Oral Session 1: Topic Highlights | ETA2022

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation

Schoenmakers Erik , Marelli Federica , Jorgensen Helle , Edward Visser W. , Moran Carla , Groeneweg Stefan , Avalos Carolina , Figg Nichola , Finigan Alison , Wali Neha , Agostini Maura , Wardle-Jones Hannah , Lyons Greta , Rusk Rosemary , Gopalan Deepa , Johannes Visser Jacob , Goddard Martin , Nashef Samer , Heijmen Robin , Clift Paul , Sinha Sanjay , Busch-Nentwich Elisabeth , Ramirez-Solis Ramiro , Persani Luca , Bennett Martin , Chatterjee Krishna

Objectives: Mutations in SECISBP2 cause deficiency of selenoproteins, resulting in a multisystem disorder with abnormal circulating thyroid hormone and selenium levels and features due to lack of specific selenoproteins or loss of antioxidant selenoenzymes. Having observed early-onset, aneurysmal thoracic aortic dilatation in four patients with this disorder, we studied zebrafish and murine Secisbp2 mutant models to determine whether the aortic phenotype and selenopro...