A5006665690- Thyroid Disorders and Treatments
- Growth Hormone and Insulin-like Growth Factors
- Congenital heart defects research
- Genetic Syndromes and Imprinting
- Neonatal Health and Biochemistry
- Thyroid Cancer Diagnosis and Treatment
- Birth, Development, and Health
- Congenital Diaphragmatic Hernia Studies
- Ion channel regulation and function
- Sexual Differentiation and Disorders
- Neonatal Respiratory Health Research
- Digestive system and related health
- Genomics and Rare Diseases
- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- Neuroscience of respiration and sleep
- Erythrocyte Function and Pathophysiology
- Genetic Associations and Epidemiology
- Selenium in Biological Systems
- Spaceflight effects on biology
- Trace Elements in Health
- Genetic Neurodegenerative Diseases
- Nuclear Structure and Function
- Folate and B Vitamins Research
University of Cambridge
2016-2025
Wellcome Trust
2015-2025
Wellcome/MRC Institute of Metabolic Science
2016-2025
Birmingham City University
2025
University of Birmingham
2019-2024
Addenbrooke's Hospital
2014-2023
Medical Research Council
2013-2023
National Institute for Health Research
2011-2019
NIHR Cambridge Biomedical Research Centre
2011-2019
University Medical Center of the Johannes Gutenberg University Mainz
2019
Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental skeletal dysplasia, severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, identified de novo heterozygous nonsense mutation in gene encoding receptor (THRA) generating mutant protein that inhibits wild-type action dominant negative manner. Our observations...
Selenium, a trace element that is fundamental to human health, incorporated into some proteins as selenocysteine (Sec), generating family of selenoproteins. Sec incorporation mediated by multiprotein complex includes insertion sequence-binding protein 2 (SECISBP2; also known SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis most 25 selenoproteins, resulting phenotype. Azoospermia, failure latter stages...
Abstract Cellular organelles provide opportunities to relate biological mechanisms disease. Here we use affinity proteomics, genetics and cell biology interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions 52 complexes. Reverse tagging, repetition purifications statistical analyses, produce high-resolution network that reveals organelle-specific...
Central hypothyroidism (CeH) is a rare form of characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due its origin and the whole clinical context, CeH represents challenging condition in practice as it suboptimal accuracy biochemical parameters for diagnosis management. Since no expert consensus or guidance this currently available, task force experts received commitment from European Thyroid Association (ETA) prepare document based on...
The first human cases (female, age 6 y; father and daughter, ages 47 11 y, respectively) with growth retardation/short stature, skeletal dysplasia, constipation, defective thyroid receptor α (TRα) have been recently described. A 45-year-old, short, overweight female cognitive impairment, epilepsy, constipation was investigated. Clinical, biochemical, radiological assessment THRA sequencing were undertaken. patient's status her biochemical physiological parameters evaluated at baseline after...
BackgroundThe thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which unknown. Here, we describe first patients identified with mutation in THRA that affects both TRα1 and compare them who have resistance owing affecting only TRα1, delineate relative roles TRα2.MethodsWe did clinical, biochemical, genetic analyses an index case her two sons. We assessed physical radiological...
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 CH GIS, systematic these eight has not previously been undertaken. Our objective was to evaluate contribution and molecular spectrum causative (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, TSHR) GIS. We screened 49 GIS from 34 ethnically diverse families,...
Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in receptor beta (THRB), is characterized by elevated levels of circulating hormones (including thyroxine), failure feedback suppression thyrotropin, and variable tissue refractoriness action. Raised energy expenditure hyperphagia are recognized features hyperthyroidism, but the effects comparable hyperthyroxinemia RTH patients unknown. Here, we show that resting (REE) was substantially...
Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical biochemical data regarding growth, puberty, metabolic outcome, well features female carriers, are scarce. Our objective to investigate characteristics associated with IGSF1 in both sexes. All patients (n = 42, 24 males) from 10 families examined the university clinics Leiden, Amsterdam, Cambridge, Milan were included this case...
Selenium is a trace element that essential for human health and incorporated into more than 25 selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery includes specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified tRNA[Ser]Sec mutation in proband who presented with variety of symptoms, including abdominal pain, fatigue, muscle weakness, low plasma levels selenium. This resulted marked reduction expression stress-related, but...
Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect.
Abstract Context: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 pathogenic mutations. Objective: We aimed to share data on largest cohort patients date formulate recommendations for clinical...
Defects in genes mediating thyroid hormone biosynthesis result dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations SLC26A7 6 unrelated families with goitrous CH and show that also occurs Slc26a7-null mice. In both species, the gene is expressed predominantly gland, loss of function associated impaired availability iodine for synthesis, partially corrected mice by supplementation. a member same transporter family as SLC26A4 (pendrin), an anion...
Summary Objective In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis ( TDH ). Context Thyroid comprises 10–15% all cases congenital hypothyroidism CH ), which is most common neonatal endocrine disorder, and might result from disruptions at any stage hormone biosynthesis. Currently seven genes NIS , TPO PDS TG IYD DUOX 2 DUOXA ) have been implicated in aetiology disease. Design As mostly inherited an autosomal recessive manner, planned conduct study...
The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the thyroid peroxidase–catalyzed iodination and coupling reactions mediating hormone biosynthesis. mutations result in dyshormonogenetic congenital hypothyroidism (CH) that may be phenotypically heterogeneous, leading to hypothesis CH severity influenced by environmental factors (e.g., dietary iodine) oligogenic modifiers variants homologous reduced form of NAD phosphate-oxidase DUOX1). However,...