A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene
Open accessAbstract
Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.
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Allan-Herndon-Dudley syndrome is caused by inactivating mutations in the SLS16A2 gene encoding MCT8 transporter for T3 thyroid hormone.
“Another disorder associated with a BBB transporter dysfunction is Allan-Herndon-Dudley syndrome caused by inactivating mutations in SLS16A2 gene encoding MCT8 transporter for T 3 thyroid hormone (156, 185).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [156]
Inactivating mutations of MCT8 in males cause serum TH abnormalities and severe neuropsychomotor impairments.
“Inactivating mutations of MCT8 in males cause serum TH abnormalities and severe neuropsychomotor impairments (Dumitrescu et al., 2004; Friesema et al., 2004).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Dumitrescu et al., 2004
Patient 2558 has a single base pair deletion in the 3rd exon of the MCT8 gene, predicted to produce a truncated and non-functional MCT8 protein that fails to migrate to the plasma membrane.
“Patient 2558 has a single base pair deletion in the 3rd exon of the MCT8 gene, predicted to produce a truncated and non-functional MCT8 protein that fails to migrate to the plasma membrane (Dumitrescu et al., 2004)”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Dumitrescu et al., 2004
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- Authors
- Dumitrescu, A. M., Liao, X.-H., Best, T. B., Brockmann, K., & Refetoff, S.
- Affiliations
- University of Chicago (US)
- University of Göttingen (DE)
- Corresponding author
- Refetoff, Samuel
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 74
- Issue
- 1
- Pages
- 168-175
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1181904
- OpenAlex
- W2017632004
- Cited by
- 706
- References
- 3
- Citations by year
- 2026: 22 · 2025: 22 · 2024: 28 · 2023: 24 · 2022: 35 · 2021: 44 · 2020: 30 · 2019: 33 · 2018: 23 · 2017: 28 · 2016: 34 · 2015: 40 · 2014: 42 · 2013: 42 · 2012: 29
- FWCI
- 17.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-17050)
- National Center for Research Resources (RR-00055, M01RR000055)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- MCT8, thyroid hormone transport, iodothyronines, X-linked inheritance, neurological abnormalities, developmental delay, spastic quadriplegia, rotary nystagmus, hearing loss, heterozygous females, genetic mutations
- MeSH terms
- Base Sequence, Brain, Child, Child, Preschool, Congenital Hypothyroidism, Electroencephalography, Female, Humans, Hypothyroidism, Male, Mutation, Pedigree, Quadriplegia, Thyroid Function Tests, Nystagmus, Congenital, Monocarboxylic Acid Transporters
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