Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine.
BACKGROUND
T(3) action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T(3) uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T(3) levels.


OBJECTIVE
The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3).


METHODS
MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T(3) uptake, 2) T(3) metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry.


RESULTS
The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8.


CONCLUSIONS
These findings support the hypothesis that the severe psychomotor retardation and elevated serum T(3) levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons.
Jansen
Jurgen
J
Department of Internal Medicine, Erasmus Medical Center, Room Ee502, Dr Molewaterplein 50, Rotterdam, The Netherlands.
Friesema
Edith C H
EC
Kester
Monique H A
MH
Milici
Carmelina
C
Reeser
Maarten
M
Grüters
Annette
A
Barrett
Timothy G
TG
Mancilla
Edna E
EE
Svensson
Johan
J
Wemeau
Jean-Louis
JL
Busi da Silva Canalli
Maria Heloisa
MH
Lundgren
Johan
J
McEntagart
Meriel E
ME
Hopper
Neil
N
Arts
Willem Frans
WF
Visser
Theo J
TJ
D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D017354:Point Mutation; D011596:Psychomotor Disorders / Q000235:genetics* / Q000378:metabolism; D022821:RNA Splice Sites; D027981:Symporters; D014162:Transfection; D014284:Triiodothyronine / Q000097:blood* / Q000493:pharmacokinetics
D018389:Codon, Nonsense; D027501:Monocarboxylic Acid Transporters; D022821:RNA Splice Sites; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine