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Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration
- Strømme, P. (author)
- Groeneweg, S. (author)
- Lima De Souza, E. C. (author)
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- Zevenbergen, C. (author)
- Torgersbråten, A. (author)
- Holmgren, A. (author)
- Gurcan, E. (author)
- Meima, M. E. (author)
- Peeters, R. P. (author)
- Visser, W. E. (author)
- Høneren Johansson, L. (author)
- Babovic, A. (author)
- Heuer, H. (author)
- Frengen, E. (author)
- Misceo, D. (author)
- Visser, T. J. (author)
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- (creator_code:org_t)
- Mary Ann Liebert Inc, 2018
- 2018
- English.
- In: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 28:11, s. 1406-1415
- Journal article (peer-reviewed)
Abstract
Subject headings
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- Background: 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. Here, the first patient with loss of OATP1C1 function is described. 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 gray and white matter degeneration and severe glucose hypometabolism. Methods: Exome sequencing of the patient and parents was performed to identify the disease-causing mutation, and the effect of the mutation was studied through a panel of in vitro experiments, including thyroxine uptake studies, immunoblotting, and immunocytochemistry. Furthermore, the clinical effects of treatment with the triiodothyronine analogue triiodothyroacetic acid (Triac) are described. 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 thyroxine 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. © Copyright 2018, Mary Ann Liebert, Inc., publishers 2018.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- brain hypometabolism
- neurodegeneration
- OATP1C1
- SLCO1C1
- thyroid hormone transport
- Triac
- asparagine
- aspartic acid
- glucose
- levothyroxine
- liothyronine
- organic anion transporter F
- thyroxine
- tiratricol
- adolescent
- Article
- bladder catheterization
- brain metabolism
- brain radiography
- case report
- clinical article
- cold tolerance
- cousin
- crystal structure
- dementia
- disease severity
- female
- glucose metabolism
- gray matter
- human
- hypothyroidism
- immunoblotting
- immunocytochemistry
- in vitro study
- JEG-3 cell line
- liothyronine blood level
- low drug dose
- missense mutation
- muscle spasm
- nerve degeneration
- priority journal
- protein function
- quality of life
- spasticity
- thyroxine blood level
- urine retention
- white matter
- whole exome sequencing
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- ref (subject category)
- art (subject category)
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- Strømme, P.
- Groeneweg, S.
- Lima De Souza, E ...
- Zevenbergen, C.
- Torgersbråten, A ...
- Holmgren, A.
- show more...
- Gurcan, E.
- Meima, M. E.
- Peeters, R. P.
- Visser, W. E.
- Høneren Johansso ...
- Babovic, A.
- Zetterberg, Henr ...
- Heuer, H.
- Frengen, E.
- Misceo, D.
- Visser, T. J.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
- MEDICAL AND HEAL ...
- and Basic Medicine
- and Neurosciences
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- Thyroid
- By the university
- University of Gothenburg
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