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Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan–Herndon–Dudley Syndrome
Author(s) -
Novara Francesca,
Groeneweg Stefan,
Freri Elena,
Estienne Margherita,
Reho Paolo,
Matricardi Sara,
Castellotti Barbara,
Visser W. Edward,
Zuffardi Orsetta,
Visser Theo J.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23140
Subject(s) - biology , genetics , mutation , physiology , bioinformatics , gene
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 V max and K m 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.