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

Introduction: 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 TRU-TCA1-1 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.

Case presentation: 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 TRU-TCA1-1 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.

Discussion/conclusion: We report on 2 members of a family with a variant in the TRU-TCA1-1 gene encoding for tRNA^[Ser]Sec. Our study suggests that this tRNA^[Ser]Sec variant is not exclusively causative of disruption in selenoprotein synthesis.