ETA2022 Oral Presentations Oral Session 11: Young Investigators / Basic (6 abstracts)
Integrated genomic, phenomic, functional and structural mapping of variants in thyroid hormone transporter MCT8
Stefan Groeneweg 1 , Ferdy Van Geest 2 , mariano martín 3 , Mafalda Dias 4 , Jonathan Frazer 4 , Rosalie Sterenborg 5 , linda de rooij 6 , anna dolcetta-capuzzo 6 , alexander teumer 7 , Marcel Meima 8 , Marco Medici 9 , juan pablo nicola 3 , debora marks 4 & W. Edward Visser 10
1Academic Center for Thyroid Diseases, Academic Center for Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands, Department of Internal Medicine, Rotterdam, Netherlands; 2Erasmus MC, Academic Center for Thyroid Disease, Department of Internal Medicine, Rotterdam, Netherlands; 3Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina; 4Department of Systems Biology, Harvard Medical School, Boston, MA, USA; 5Academic Center for Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands, Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands, Netherlands; 6Academic Center for Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center Rotterdam, The Netherlands; 7Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany, Dzhk (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany; 8Dept of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, Rotterdam, Netherlands; 9Radboud University Medical Center, Nijmegen, Erasmus Medical Center, Rotterdam, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands; 10Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands
Background: MCT8 deficiency is caused by loss-of-function (LoF) mutations in thyroid hormone (TH) transporter MCT8. Patients have developmental delay and abnormal thyroid function tests (TFTs). The large phenotypic variability is not understood. Moreover, phenotypes arising from LoF mutations could be employed to enhance understanding of physiology in the general population. Also, computational disease variant classifiers have poor predictive power to ascertain impact of MCT8 variants. We conducted a generalizable approach that addresses all abovementioned challenges.
Methods: We systematically integrated genetic, clinical and biochemical data from 371 patients with MCT8 deficiency, accrued through combination of data from our well-phenotyped global cohort and meta-analysis of all reported cases. We assessed the impact of common genetic variation in MCT8 on TFTs in ~70k individuals. We evaluated impact of 108 patient mutations and 304 MCT8 variants in a full alanine-scanning by TH transport assays. We linked three distinct LoF classes (mild, moderate, severe) to phenotypic outcomes and mapped all variants onto our homology model. Utilizing these data and conservation analyses, an MCT8 deficiency-specific variant classifier was constructed using artificial intelligence methods.
Findings: Linking the different LoF classes to phenotypic outcomes, we observed a clear genotype-phenotype relationship across a range of disease features. Functional impact of variants strongly associated with survival of patients (median survival mild LoF: 71yrs; moderate LoF: 60yrs; severe LoF: 21.4yrs). Similar observations were noted for developmental (e.g. motor function), clinical (e.g. seizures) and biochemical (e.g. fT4, but not T3) features. Beneficial effects of the TH analogue Triac on several disease outcomes were independent of LoF category. By cross-referencing functional alanine-scanning data with patient mutants, we could infer the underlying mechanisms for the majority of variants. Our MCT8-specific classifier largely outperformed (AUC 0.95) commonly used prediction tools. Common genetic variation in MCT8 was associated with lower serum fT4, but not with TSH or T3 concentrations, resembling the genotype-phenotype relationships in patients.
Interpretation: The combination of deep phenotyping data from patients with MCT8 deficiency with a battery of functional and computational tests and with outcomes in population cohorts, enabled us to: (i) understand the divergent clinical phenotypes of MCT8 deficiency, (ii) assess therapy effectiveness, (iii) advance structural insights of MCT8, (iv) create a high-quality disease variant classifier, together also leveraging information on the role of MCT8 in non-affected individuals in the population.
Volume 84
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more