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Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series
CONTEXT: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823235/ https://www.ncbi.nlm.nih.gov/pubmed/33141165 http://dx.doi.org/10.1210/clinem/dgaa795 |
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author | van Geest, Ferdy S Meima, Marcel E Stuurman, Kyra E Wolf, Nicole I van der Knaap, Marjo S Lorea, Cláudia F Poswar, Fabiano O Vairo, Filippo Brunetti-Pierri, Nicola Cappuccio, Gerarda Bakhtiani, Priyanka de Munnik, Sonja A Peeters, Robin P Visser, W Edward Groeneweg, Stefan |
author_facet | van Geest, Ferdy S Meima, Marcel E Stuurman, Kyra E Wolf, Nicole I van der Knaap, Marjo S Lorea, Cláudia F Poswar, Fabiano O Vairo, Filippo Brunetti-Pierri, Nicola Cappuccio, Gerarda Bakhtiani, Priyanka de Munnik, Sonja A Peeters, Robin P Visser, W Edward Groeneweg, Stefan |
author_sort | van Geest, Ferdy S |
collection | PubMed |
description | CONTEXT: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes. METHODS: We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts. RESULTS: Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated. CONCLUSIONS: Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8. |
format | Online Article Text |
id | pubmed-7823235 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-78232352021-01-27 Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series van Geest, Ferdy S Meima, Marcel E Stuurman, Kyra E Wolf, Nicole I van der Knaap, Marjo S Lorea, Cláudia F Poswar, Fabiano O Vairo, Filippo Brunetti-Pierri, Nicola Cappuccio, Gerarda Bakhtiani, Priyanka de Munnik, Sonja A Peeters, Robin P Visser, W Edward Groeneweg, Stefan J Clin Endocrinol Metab Clinical Research Articles CONTEXT: Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes. METHODS: We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts. RESULTS: Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A>G;p.(His575Arg) or c.1796A>G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated. CONCLUSIONS: Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8. Oxford University Press 2020-11-03 /pmc/articles/PMC7823235/ /pubmed/33141165 http://dx.doi.org/10.1210/clinem/dgaa795 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Clinical Research Articles van Geest, Ferdy S Meima, Marcel E Stuurman, Kyra E Wolf, Nicole I van der Knaap, Marjo S Lorea, Cláudia F Poswar, Fabiano O Vairo, Filippo Brunetti-Pierri, Nicola Cappuccio, Gerarda Bakhtiani, Priyanka de Munnik, Sonja A Peeters, Robin P Visser, W Edward Groeneweg, Stefan Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series |
title | Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series |
title_full | Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series |
title_fullStr | Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series |
title_full_unstemmed | Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series |
title_short | Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series |
title_sort | clinical and functional consequences of c-terminal variants in mct8: a case series |
topic | Clinical Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823235/ https://www.ncbi.nlm.nih.gov/pubmed/33141165 http://dx.doi.org/10.1210/clinem/dgaa795 |
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