Inherited Selenocysteine Transfer RNA Mutation: Clinical and Hormonal Evaluation of 2 Patients

Abstract

<b><i>Introduction:</i></b> Iodothyronine deiodinases are selenoproteins with the amino acid selenocysteine (Sec) introduced into the position of a TGA stop codon by a complex machinery involving tRNA^[Ser]Sec when a cis-acting Sec-insertion sequence element is present in the 3′ end of the mRNA. Recently, a variant in the <i>TRU-TCA1-1</i> gene encoding for tRNA^[Ser]Sec was reported, which resulted in reduced expression of stress-related selenoproteins. The proband presented with multisystem symptoms, euthyroid hyperthyroxinemia, and selenium deficiency. Here, we describe 2 new members of a family harboring the same tRNA^[Ser]Sec variant. <b><i>Case Presentation:</i></b> A 13-year-old patient was seen for Hashimoto’s disease with high FT3 (4.6 pg/mL, normal range 2–4.2 pg/mL) and normal FT4 and TSH concentrations. He had no clinical complaints. During a 6-year clinical and hormonal follow-up, the index patient was not treated, FT3 decreased, FT4 increased, and serum TSH stayed in the normal range resulting in a euthyroid hyperthyroxinemia. Reverse T3 concentration was significantly increased at the last visit (19 years and 4 months). At the last evaluation, the total selenium level was low (91 μg/L, normal range 95–125). DNA sequencing identified a germinal homozygous variant (C65G) in the <i>TRU-TCA1-1</i> gene. During follow-up, no additional clinical symptom was observed in the absence of any treatment. The same germinal tRNA^[Ser]Sec variant was identified at heterozygous state in his father, who had normal thyroid function tests except a moderately increased reverse T3 concentration, with increased total selenium (143 μg/L) level. In both patients, the expression of stress-related selenoprotein GPX3 was in the low-normal range (168 and 180 IU/L, respectively, normal range: 150–558 IU/L). We did not find any significant biological abnormalities evocative of other selenoprotein deficiencies. <b><i>Discussion/Conclusion:</i></b> We report on 2 members of a family with a variant in the <i>TRU-TCA1-1</i> gene encoding for tRNA^[Ser]Sec. Our study suggests that this tRNA^[Ser]Sec variant is not exclusively causative of disruption in selenoprotein synthesis.