Petter Strømme1,2, Stefan Groeneweg3, Elaine C Lima de Souza3, Chantal Zevenbergen3, Anette Torgersbråten4, Asbjørn Holmgren4, Ebrar Gurcan3, Marcel E Meima3, Robin P Peeters3, W Edward Visser3, Linda Høneren Johansson1, Almira Babovic5, Henrik Zetterberg6,7,8,9, Heike Heuer10, Eirik Frengen4, Doriana Misceo4, Theo J Visser3. 1. 1 Division of Pediatric and Adolescent Medicine; Oslo University Hospital , Oslo, Norway . 2. 2 Faculty of Medicine, University of Oslo , Oslo, Norway . 3. 3 Erasmus Medical Center, Department of Internal Medicine, Academic Center for Thyroid Diseases , Rotterdam, The Netherlands . 4. 4 Department of Medical Genetics, Oslo University Hospital and University of Oslo , Oslo, Norway . 5. 5 Department of Nuclear Medicine; Oslo University Hospital , Oslo, Norway . 6. 6 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal, Sweden . 7. 7 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg , Mölndal, Sweden . 8. 8 Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London, United Kingdom . 9. 9 UK Dementia Research Institute at UCL , London, United Kingdom . 10. 10 Department of Endocrinology, University of Duisburg-Essen , Essen, Germany .
Abstract
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.
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 humanOATP1C1deficiency compatible with brain-specific hypothyroidism and neurodegeneration.
Entities:
Keywords:
OATP1C1; SLCO1C1; Triac; brain hypometabolism; neurodegeneration; thyroid hormone transport
Authors: Antonio C Bianco; Alexandra Dumitrescu; Balázs Gereben; Miriam O Ribeiro; Tatiana L Fonseca; Gustavo W Fernandes; Barbara M L C Bocco Journal: Endocr Rev Date: 2019-08-01 Impact factor: 19.871
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