Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic
fingerprint that underlies associated clinical syndromes
#MMPMID25569702
McAninch EA
; Jo S
; Preite NZ
; Farkas E
; Mohácsik P
; Fekete C
; Egri P
; Gereben B
; Li Y
; Deng Y
; Patti ME
; Zevenbergen C
; Peeters RP
; Mash DC
; Bianco AC
J Clin Endocrinol Metab
2015[Mar]; 100
(3
): 920-33
PMID25569702
show ga
CONTEXT: 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. DESIGN, SETTING, PATIENTS: 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.
|*Polymorphism, Single Nucleotide
[MESH]
|*Transcriptome
[MESH]
|Adult
[MESH]
|Alanine/genetics
[MESH]
|Amino Acid Substitution
[MESH]
|Case-Control Studies
[MESH]
|Cerebral Cortex/metabolism/pathology
[MESH]
|Gene Frequency
[MESH]
|HEK293 Cells
[MESH]
|HeLa Cells
[MESH]
|Humans
[MESH]
|Iodide Peroxidase/*genetics
[MESH]
|Iodothyronine Deiodinase Type II
[MESH]
|Male
[MESH]
|Microarray Analysis
[MESH]
|Nervous System Diseases/*genetics/pathology
[MESH]
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