Endocrine Abstracts

A multisystem selenoprotein disorder with a thyroid signature

Nadia Schoenmakers¹, Erik Schoenmakers¹, Maura Agostini¹, Catherine Mitchell¹, Laura Papp², Odelia Rajanayagam¹, Raja Padidela³, Rainer Doffinger⁴, Jian’an Luan⁵, Jun Lu⁶, Irene Campi¹, Hannah Burton¹, Francesco Muntoni⁷, Dominic O’ Donovan⁸, Andrew Dean⁸, Anne Warren⁸, Pascale Guicheney⁹, Rebecca Fitzgerald¹⁰, Alasdair Coles¹¹, Hill Gaston¹², Arne Holmgren⁶, Marcus S. Cooke¹³, David Halsall¹⁴, Nicholas Wareham⁵, Paolo Beck-Peccoz¹⁵, Arthur Ogunko¹⁶, Mehul Dattani³, Mark Gurnell¹ & Krishna Chatterjee¹

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.

---

Endocrine Abstracts (2010) 21 OC3.5