Mutations in the thyroid hormone transporter SLC16A2 (MCT8) cause the Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and peripheral thyrotoxicosis. Here, we report three newly identified AHDS patients. Previously documented mutations were identified in probands 1 (p.R271H) and 2 (p.G564R), resulting in a severe clinical phenotype. A novel mutation (p.G564E) was identified in proband 3, affecting the same Gly564 residue, but resulting in a relatively mild clinical phenotype. Functional analysis in transiently transfected COS-1 and JEG-3 cells showed a near-complete inactivation of TH transport for p.G564R, whereas considerable cell-type-dependent residual transport activity was observed for p.G564E. Both mutants showed a strong decrease in protein expression levels, but differentially affected Vmax and Km values of T3 transport. Our findings illustrate that different mutations affecting the same residue may have a differential impact on SLC16A2 transporter function, which translates into differences in severity of the clinical phenotype.

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Human Mutation
Erasmus MC: University Medical Center Rotterdam

Novara, F. (Francesca), Groeneweg, S., Freri, E. (Elena), Estienne, M. (Margherita), Reho, P. (Paolo), Matricardi, S. (Sara), … Visser, T.J. (Theo J.). (2017). Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome. Human Mutation. doi:10.1002/humu.23140