title: Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes.
abstract: BACKGROUND
  A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated.
  
  
  OBJECTIVE
  To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism.
  
  
  METHODS
  Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2.
  
  
  RESULTS
  The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine.
  
  
  CONCLUSIONS
  Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.
authors.affiliation: Division of Endocrinology and Metabolism (E.A.M., S.J., N.Z.P., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Endocrine Neurobiology (E.F., P.M., C.F., P.E., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083, Hungary; Péter Pázmány Catholic University (E.F.), Multidisciplinary Doctoral School of Sciences and Technology, Budapest, H-1083 Hungary; Semmelweis University (P.M., P.E.), János Szentágothai PhD School of Neurosciences, Budapest, H-1085 Hungary; Division of Endocrinology (C.F.), Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts 02111; Department of Medicine (Y.L., Y.D.), Rush University Medical Center, Chicago, Illinois 60612; Joslin Diabetes Center (M.E.P.), Harvard Medical School, Boston, Massachusetts 02215; Division of Endocrinology (C.Z., R.P.P.), Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Department of Neurology (D.C.M.), University of Miami Miller School of Medicine, Miami, Florida 33136.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McAninch
authors.forename: Sungro
authors.initials: S
authors.lastname: Jo
authors.forename: Nailliw Z
authors.initials: NZ
authors.lastname: Preite
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Farkas
authors.forename: Petra
authors.initials: P
authors.lastname: Mohácsik
authors.forename: Csaba
authors.initials: C
authors.lastname: Fekete
authors.forename: Péter
authors.initials: P
authors.lastname: Egri
authors.forename: Balázs
authors.initials: B
authors.lastname: Gereben
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Youping
authors.initials: Y
authors.lastname: Deng
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Patti
authors.forename: Chantal
authors.initials: C
authors.lastname: Zevenbergen
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
mesh_terms: D000328:Adult; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005787:Gene Frequency; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D013912:Threonine / Q000235:genetics; D013959:Thyroid Diseases / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D000409:Alanine; D007453:Iodide Peroxidase; D013912:Threonine; D000097564:Iodothyronine Deiodinase Type II