Mutated thyroid hormone transporter OATP1C1 associates with severe brain hypometabolism and juvenile neurodegeneration

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

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