Clinical and Molecular Characteristics of SLC16A2 (MCT8) Mutations in Three Families with the Allan-Herndon-Dudley Syndrome.
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 Vmaxand Kmvalues 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.
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Francesca
F
Novara
Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
Stefan
S
Groeneweg
Department of Pediatric Neuroscience, Foundation I.R.C.C.S. Neurological Institute "C. Besta", Milan, Italy.
Elena
E
Freri
Department of Pediatric Neuroscience, Foundation I.R.C.C.S. Neurological Institute "C. Besta", Milan, Italy.
Margherita
M
Estienne
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Paolo
P
Reho
Department of Pediatric Neuroscience, Foundation I.R.C.C.S. Neurological Institute "C. Besta", Milan, Italy.|Department of Pediatrics, University of Chieti, Chieti, Italy.
Sara
S
Matricardi
SOSD Genetica delle Malattie Neurodegenerative e Metaboliche, U.O Patologia Clinica, Foundation I.R.C.C.S. Neurological Institute "C. Besta", Milan, Italy.
Barbara
B
Castellotti
Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
W Edward
WE
Visser
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Orsetta
O
Zuffardi
Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
Theo J
TJ
Visser
D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009123:Muscle Hypotonia / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D009133:Muscular Atrophy / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D027981:Symporters
D015415:Biomarkers; D027501:Monocarboxylic Acid Transporters; C090735:SLC16A2 protein, human; D027981:Symporters
Allan-Herndon-Dudley Syndrome; MCT8; SLC16A2; thyroid hormone transport