title: Functional analysis of novel genetic variation in the thyroid hormone activating type 2 deiodinase.
abstract: BACKGROUND
  Thyroid hormones (TH) are important for normal brain development and abnormal TH regulation in the brain results in neurocognitive impairments. The type 2 deiodinase (D2) is important for local TH control in the brain by generating the active hormone T3 from its precursor T4. Dysfunction of D2 likely results in a neurocognitive phenotype. No mutations in D2 have been reported yet.
  
  
  OBJECTIVE
  The objective of the study was to identify D2 mutations in patients with intellectual disability and to test their functional consequences.
  
  
  METHODS
  The patients were selected from the multicenter Thyroid Origin of Psychomotor Retardation study, which is a cohort of 946 subjects with unexplained intellectual disability. Based on characteristic serum TH values, the coding region of the DIO2 gene was sequenced in 387 patients. Functional consequences were assessed by in vitro D2 assays or intact cell metabolism studies using cells transfected with wild-type or mutant D2.
  
  
  RESULTS
  Sequence analysis revealed two heterozygous mutations: c.11T>A (p.L4H) in three subjects and c.305C>T (p.T102I) in one subject. Sequence analysis of family members revealed several carriers, but no segregation was observed with thyroid parameters or neurocognitive phenotype. Extensive tests with different in vitro D2 assays did not show differences between wild-type and mutant D2.
  
  
  CONCLUSIONS
  This study describes the identification and functional consequences of novel genetic variation in TH activating enzyme D2. Family studies and functional tests suggest that these variants do not underlie the neurocognitive impairment. Altogether our data provide evidence of the existence of rare but apparently harmless genetic variants of D2.
authors.affiliation: Department of Internal Medicine (C.Z., W.K., R.P.P., M.M., Y.B.d.R., M.E.M., T.J.V., W.E.V.), Rotterdam Thyroid Center (C.Z., W.K., R.P.P., M.M., M.E.M., T.J.V., W.E.V.), Department of Clinical Chemistry (Y.B.d.R.), Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands; Prinsenstichting (S.A.H.), Kwadijkerpark 8, 1444 JE Purmerend, The Netherlands; Ipse De Bruggen (H.G., E.B.), Spoorlaan 19, 2471 PB Zwammerdam, The Netherlands; Vanboeijenoord (G.d.K.), Industrieweg 14-16, 9400 RA Assen, The Netherlands; 's Heeren Loo Groot Schuilenburg (K.H.d.W.), Laan Van Groot Schuylenburg 310-320, 7325 BG Apeldoorn, The Netherlands; and Department of Internal Medicine (R.L.), Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: Chantal
authors.initials: C
authors.lastname: Zevenbergen
authors.forename: Wim
authors.initials: W
authors.lastname: Klootwijk
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.forename: Yolanda B
authors.initials: YB
authors.lastname: de Rijke
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Huisman
authors.forename: Henk
authors.initials: H
authors.lastname: Goeman
authors.forename: Erik
authors.initials: E
authors.lastname: Boot
authors.forename: Gerda
authors.initials: G
authors.lastname: de Kuijper
authors.forename: K Herman
authors.initials: KH
authors.lastname: de Waal
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Meima
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: W Edward
authors.initials: WE
authors.lastname: Visser
mesh_terms: D006801:Humans; D008607:Intellectual Disability / Q000097:blood / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013963:Thyroid Hormones / Q000097:blood*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D013963:Thyroid Hormones; D000097564:Iodothyronine Deiodinase Type II