Chantal Zevenbergen1, Stefan Groeneweg1, Sigrid M A Swagemakers2,3, Arthur de Jong4, Evita Medici-Van den Herik5, Madzy Rispens6, Wim Klootwijk1, Marco Medici1, Yolanda B de Rijke7, Marcel E Meima1, P Reed Larsen8, Laurent Chavatte9, Deon Venter10, Robin P Peeters1, Peter J Van der Spek2,3, W Edward Visser1. 1. Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands. 2. Department of Bioinformatics, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands. 3. Department of Pathology, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands. 4. Gemiva-SVG Group, Zoeterwoude, Netherlands. 5. Department of Child Neurology, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands. 6. 's Heeren Loo, Noorderhaven, Netherlands. 7. Department of Clinical Chemistry, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands. 8. Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 9. Centre International de Recherche en Infectiologie, CIRI, INSERM U1111, CNRS/ENS/UCBL1 UMR5308, Lyon, France. 10. Department of Pathology, Mater Health Services, South Brisbane, Queensland, Australia.
Abstract
CONTEXT: Thyroid hormone is important for normal brain development. The type 2 deiodinase (D2) controls thyroid hormone action in the brain by activating T4 to T3. The enzymatic activity of D2 depends on the incorporation of selenocysteine for which the selenocysteine-insertion sequence (SECIS) element located in the 3' untranslated region is indispensable. We hypothesized that mutations in the SECIS element could affect D2 function, resulting in a neurocognitive phenotype. OBJECTIVE: To identify mutations in the SECIS element of DIO2 in patients with intellectual disability and to test their functional consequences. DESIGN, SETTING, AND PATIENTS: The SECIS element of DIO2 was sequenced in 387 patients with unexplained intellectual disability using a predefined pattern of thyroid function tests. SECIS element read-through in wild-type or mutant D2 was quantified by a luciferase reporter system in transfected cells. Functional consequences were assessed by quantifying D2 activity in cell lysate or intact cell metabolism studies. RESULTS: Sequence analysis revealed 2 heterozygous mutations: c.5703C>T and c.5730A>T, which were also present in the unaffected family members. The functional evaluation showed that both mutations did not affect D2 enzyme activity in cell lysates or intact cells, although the 5730A>T mutation decreased SECIS element read-through by 75%. In the patient harboring the c.5730A>T variant, whole genome sequencing revealed a pathogenic deletion of the STXBP1 gene. CONCLUSIONS: We report on two families with mutations in the SECIS element of D2. Although functional analysis showed that nucleotide 5730 is important for normal SECIS element read-through, the two variants did not segregate with a distinct phenotype.
CONTEXT: Thyroid hormone is important for normal brain development. The type 2 deiodinase (D2) controls thyroid hormone action in the brain by activating T4 to T3. The enzymatic activity of D2 depends on the incorporation of selenocysteine for which the selenocysteine-insertion sequence (SECIS) element located in the 3' untranslated region is indispensable. We hypothesized that mutations in the SECIS element could affect D2 function, resulting in a neurocognitive phenotype. OBJECTIVE: To identify mutations in the SECIS element of DIO2 in patients with intellectual disability and to test their functional consequences. DESIGN, SETTING, AND PATIENTS: The SECIS element of DIO2 was sequenced in 387 patients with unexplained intellectual disability using a predefined pattern of thyroid function tests. SECIS element read-through in wild-type or mutant D2 was quantified by a luciferase reporter system in transfected cells. Functional consequences were assessed by quantifying D2 activity in cell lysate or intact cell metabolism studies. RESULTS: Sequence analysis revealed 2 heterozygous mutations: c.5703C>T and c.5730A>T, which were also present in the unaffected family members. The functional evaluation showed that both mutations did not affect D2 enzyme activity in cell lysates or intact cells, although the 5730A>T mutation decreased SECIS element read-through by 75%. In the patient harboring the c.5730A>T variant, whole genome sequencing revealed a pathogenic deletion of the STXBP1 gene. CONCLUSIONS: We report on two families with mutations in the SECIS element of D2. Although functional analysis showed that nucleotide 5730 is important for normal SECIS element read-through, the two variants did not segregate with a distinct phenotype.