Stromme, P;
Groeneweg, S;
Lima de Souza, EC;
Zevenbergen, C;
Torgersbråten, A;
Holmgren, A;
Gurcan, E;
... Visser, TJ; + view all
(2018)
Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration.
Thyroid
, 28
(11)
pp. 1406-1415.
10.1089/thy.2018.0595.
Preview |
Text
Zetterberg_Strømme.pdf - Accepted Version Download (911kB) | Preview |
Abstract
Context Thyroid hormones (TH) are essential for brain development and function. The TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporter1 C1 (OATP1C1) facilitate the transport of TH across the blood-brain-barrier and into glia and neuronal cells in the brain. Loss of MCT8 function causes Allan-Herndon-Dudley syndrome (AHDS, OMIM 300523) characterized by severe intellectual and motor disability due to cerebral hypothyroidism. We describe the first patient with loss of OATP1C1 function. The patient is a 15.5-year-old girl with normal development in the first year of life, who gradually developed dementia with spasticity and intolerance to cold. Brain imaging demonstrated grey and white matter degeneration and severe glucose hypometabolism. Methods We performed exome sequencing of the patient and parents to identify the disease-causing mutation and studied the effect of the mutation through a panel of in vitro experiments, including T4 uptake studies, immunoblotting, and immunocytochemistry. Furthermore, we describe the clinical effects of treatment with the T3 analogue triiodothyroacetic acid (Triac). Results Exome sequencing identified a homozygous missense mutation in OATP1C1 changing the highly conserved aspartic acid 252 to asparagine (D252N). In vitro, the mutated OATP1C1 displays impaired plasma membrane localization and decreased cellular T4 uptake. After treatment with Triac the clinical condition improved in several domains. Conclusions This is the first report of human OATP1C1 deficiency, compatible with brain-specific hypothyroidism and neurodegeneration.
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
