2014-11-01
Functional analysis of novel genetic variation in the thyroid hormone activating type 2 deiodinase
Publication
Publication
Journal of Clinical Endocrinology and Metabolism , Volume 99 - Issue 11 p. E2429- E2436
Context: 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.
Design, Setting, and Patients: 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 heterozygousmutations: c.11TA (p.L4H) in three subjects
and c.305CT (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.
Conclusion: 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 neurocognitiveimpairment. Altogether our data provide evidence of the existence of rare
but apparently harmless genetic variants of D2.
Additional Metadata | |
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doi.org/10.1210/jc.2014-2281, hdl.handle.net/1765/80152 | |
Journal of Clinical Endocrinology and Metabolism | |
Organisation | Erasmus MC: University Medical Center Rotterdam |
Zevenbergen, C., Klootwijk, W., Peeters, R., Medici, M., de Rijke, Y., Huisman, S., … Visser, E. (2014). Functional analysis of novel genetic variation in the thyroid hormone activating type 2 deiodinase. Journal of Clinical Endocrinology and Metabolism, 99(11), E2429–E2436. doi:10.1210/jc.2014-2281 |