BACKGROUND: The monocarboxylate transporter 8 (MCT8) is a member of the major 
facilitator superfamily (MFS) and transports specificly iodothyronines. MCT8 
mutations are the underlying cause of a syndrome of severe X-linked psychomotor 
retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is 
characterized by abnormally high T3, low/normal T4 serum levels and slightly 
elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are 
known and they are valuable indicators of important regions for structural and 
functional MCT8 properties.
METHODS: We designed a structural human MCT8 model and studied reported 
pathogenic missense mutations with focus on the estimation of those amino acid 
positions which are probably sensitive for substrate transport. Furthermore, 
assuming similarities between determinants of T3 binding observed in the 
published crystal structure of the thyroid hormone receptor beta occupied by its 
ligand T3 and the structural MCT8 model, we explore potential T3 binding sites 
in the MCT8 substrate channel cavity.
RESULTS: We found that all known pathogenic missense mutations are located 
exclusively in the transmembrane helices and to a high degree at conserved 
residues among the MCT family. Furthermore, mutations either of or to 
prolines/glycines are located mainly at helices 9-12 and are expected to cause 
steric clashes or structural misfolding. In contrast, several other mutations 
are close to the potential substrate channel and affected amino acids are likely 
involved in the switching mechanism between different transporter conformations. 
Finally, three potential substrate binding sites are predicted for MCT8.
CONCLUSIONS: Naturally occurring mutations of MCT8 provide molecular insights 
into protein regions important for protein folding, substrate binding and the 
switching mechanism during substrate transport. Future studies guided by this 
information should help to clarify structure-function relationships at MCT8 
which may bear broader relevance for other members of the MCT family. This 
includes decoding of the complete set of transport-sensitive residue positions 
and description of structural re-arrangements during transport.