SFEBES2009 Oral Communications Young Endocrinologists prize session (8 abstracts)
A multisystem selenoprotein disorder with a thyroid signature
Nadia Schoenmakers 1 , Erik Schoenmakers 1 , Maura Agostini 1 , Catherine Mitchell 1 , Laura Papp 2 , Odelia Rajanayagam 1 , Raja Padidela 3 , Rainer Doffinger 4 , Jian’an Luan 5 , Jun Lu 6 , Irene Campi 1 , Hannah Burton 1 , Francesco Muntoni 7 , Dominic O’ Donovan 8 , Andrew Dean 8 , Anne Warren 8 , Pascale Guicheney 9 , Rebecca Fitzgerald 10 , Alasdair Coles 11 , Hill Gaston 12 , Arne Holmgren 6 , Marcus S. Cooke 13 , David Halsall 14 , Nicholas Wareham 5 , Paolo Beck-Peccoz 15 , Arthur Ogunko 16 , Mehul Dattani 3 , Mark Gurnell 1 & Krishna Chatterjee 1
1Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Queensland Institute for Medical Research, Brisbane, Queensland, Australia; 3Great Ormond Street Children’s Hospital, London, UK; 4Department of Clinical Immunology, University of Cambridge, Cambridge, UK; 5MRC Epidemiology Unit, Cambridge, UK; 6Medical Nobel Institute for Biochemistry, Karolinska Institute, Stockholm, Sweden; 7UCL Institute of Child Health, Dubowitz Neuromuscular Centre, London, UK; 8Department of Histopathology, University of Cambridge, Cambridge, UK; 9Institut de Myologie, Paris, France; 10MRC Cancer Cell Unit, Cambridge, UK; 11Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; 12Department of Medicine, University of Cambridge, Cambridge, UK; 13Department of Cancer Studies, Molecular Medicine and Genetics, University of Leicester, Leicester, UK; 14Department of Clinical Biochemistry, University of Cambridge, Cambridge, UK; 15Department of Medical Sciences, Fondazione Policlinico, IRCCS, Milan, Italy; 16Darrent Valley Hospital, Kent, UK.
Selenocysteine insertion sequence-binding protein 2 (SECISBP2) mediates translational incorporation of selenocysteine into 25 known human selenoproteins, including iodothyronine deiodinases. Two unrelated male subjects, aged 36 years (P1) and 3.6 years (P2), exhibited markedly elevated free thyroxine (fT4), normal/low free triiodothyronine (fT3), but normal thyrotropin (TSH) levels, indicating reduced T4 to T3 conversion:
| Parameter | P1 | P2 |
| fT4 pmol/l (9–20) | 41.1 | 35.0 |
| fT3 pmol/l (3–7.5) | 3.8 | 2.3 |
| TSH mU/l (0.4–4.0) | 0.49 | 1.10 |
However, low circulating glutathione peroxidase and selenoprotein P levels suggested a more widespread selenoprotein deficiency, and both patients are compound heterozygous for defects in SECISBP2.
P1 is azoospermic, with reduced levels of testis-enriched selenoproteins (GPx4, TGR, SELV) mediating spermatogenic arrest. He has a muscular dystrophy with clinical (axial muscle weakness) and pathological (excess type 1 fibres, minicores, low SELN) features similar to known SEPN1 mutation myopathies. He is markedly photosensitive, which is linked to dermal deficiency of antioxidant selenoenzymes (GPx1, TrxR, SELX) with increased cellular reactive oxygen species (ROS), membrane lipid peroxidation and oxidative DNA damage. Reduction of immune cell antioxidant defence is associated with impaired T cell proliferation and shortened telomeric DNA; the latter may mediate his borderline anaemia and lymphopenia, analogous to aplastic anaemia found in human telomerase deficiency. He has increased adipose mass, but enhanced insulin sensitivity with increased ERK phosphorylation in skin fibroblasts. P2 is also deficient in tissue-specific selenoproteins (e.g. GPx4, SELN) and antioxidant selenoenzymes. He too has myopathy, increased adipose mass and insulin sensitivity. Both patients also demonstrate reduced levels of other selenoproteins (e.g. SELH, SELI, SELT, SEPW) whose functions are unknown.
Thus, we describe a multisystem disorder, with a distinctive biochemical thyroid signature, involving defective synthesis of many selenoproteins, which highlights their roles in diverse biological processes and may elucidate hitherto unknown functions of members of the selenoproteome.
Note: All authors listed in this version do not appear in the printed version.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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