Dataset Information

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.

ABSTRACT: Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2'-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.

SUBMITTER: Schoenmakers E

PROVIDER: S-EPMC4767355 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.

Schoenmakers Erik E Carlson Bradley B Agostini Maura M Moran Carla C Rajanayagam Odelia O Bochukova Elena E Tobe Ryuta R Peat Rachel R Gevers Evelien E Muntoni Francesco F Guicheney Pascale P Schoenmakers Nadia N Farooqi Sadaf S Lyons Greta G Hatfield Dolph D Chatterjee Krishna K

The Journal of clinical investigation 20160208 3

Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a ma ...[more]

PMID: 26854926

Similar Datasets

Project description:IntroductionIodothyronine 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 presentationA 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/conclusionWe 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.

Dataset Information

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.

Publications

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets