Endocrine Abstracts (2009) 23 OC1.4

A multisystem disorder associated with defective selenoprotein synthesis and a thyroid signature

R Padidela1, N Al-Ali2, E Schoenmakers2, M Agostini2, O Rajanayagam2, M T Dattani1 & V K K Chatterjee2

1Developmental Endocrinology Research Group, Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; 2Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

The superfamily of ~25 human selenoproteins includes antioxidant and oxidoreductase enzymes together with other proteins of unknown function. We describe a child with a multisystem disorder involving deficiencies of several selenoproteins, identified on the basis of abnormal thyroid function.

A 3.6-year-old male was referred with elevated free thyroxine (FT4 – 44.4 pmol/l (N 12–22)), low free triiodothyronine (FT3 – 1.9 pmol/l (N 5.2–10.2)) and normal TSH (2.9 mU/l (N<6)) concentrations, indicating reduced T4 to T3 conversion. Deiodinases (DIOs) are selenoenzymes, and low circulating selenium 0.06 μmol/l (N 0.5–1.3), undetectable glutathione peroxidase (GPx) and reduced selenoprotein P concentrations, suggested multiple selenoprotein defects. Incorporation of selenocysteine (Sec) during protein synthesis requires binding of a multiprotein complex that includes the selenocysteine insertion sequence binding protein 2 (SECISBP2) to a stem loop structure in the 3′-untranslated region of their mRNAs. SECISBP2 gene sequencing identified a heterozygous missense mutation (Cys691Arg) in the proband and his mother, involving a highly conserved cysteine residue within the C-terminal RNA-binding domain of this protein; an additional defect, involving aberrant SECISBP2 splicing, was identified in the proband’s other allele and his father.

Additional features in the index case included short stature (height −2.4SDS), mild global developmental delay, and proximal muscle weakness. Selenoprotein N (SEPN) is essential for normal muscle function, and SEPN expression was markedly reduced in cultured fibroblasts from the proband. Progressive failure to thrive in infancy led to a diagnosis of eosinophilic colitis at 24 months. Body composition was abnormal, with markedly increased fat mass (+2SDS), but associated with a propensity to non-ketotic fasting hypoglycaemia requiring supplementary enteral nutrition. Auditory assessment suggested bilateral high frequency hearing loss, which is also a feature in DIO2 null mice. Normalisation of FT3 levels following commencement of liothyronine treatment, was associated with improvement in linear growth, speech and neurodevelopment.

This unusual genetic disorder highlights the diverse roles of selenoproteins in biological processes and may also be a useful paradigm to model consequences of human selenium deficiency.

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