Transporter defects; a study of novel mechanisms of thyroid hormone resistance with dramatic consequences.

Recently, a novel syndrome combining severe psychomotor retardation and
elevated levels of the bioactive hormone T3, caused by mutations in the MCT8
thyroid hormone transporter has been discovered by our laboratory. MCT8 is
important for T3 entry in different tissues, in particular in central neurons
which are the primary target for thyroid hormone*s crucial action during brain
development. This T3 is provided by outer ring deiodination of the prohormone
T4 by the type 2 deiodinase (D2) expressed in neighbouring astrocytes. T3 acts
on nuclear receptors in neurons, and this action is terminated by the inner
ring deiodinaton of T3 by the type 3 deiodinase (D3) also expressed in these
cells. A defect in MCT8 results in a lack of T3 supply to neurons and, thus, in
impaired neurological development and reduced T3 clearance. This syndrome
represents a novel mechanism of thyroid hormone resistance. Until now, thyroid
hormone resistance has been associated only with mutations in the beta type T3
receptor.
Two other thyroid hormone-specific transporters have recently been identified
in brain, of which OATP1C1 is located in capillaries and astrocytes, and MCT10
has an unknown distribution. We hypothesize that also mutations in these
transporters or in D2 or D3 result in abnormal brain and serum thyroid hormone
levels as well as impaired neurological development.

Our project focuses on the function of transporters and deiodinases in the
(dys)regulation of intracellular T3 levels in patients with psychomotor
retardation and abnormal serum thyroid hormone levels. The main objectives of
our study are:
1. To determine the role of thyroid hormone related candidate genes in the
development of psychomotor retardation.
2. To determine the functional consequences of the mutations found in the
patients on transporter and deiodinase activities.

This observational study will be done by screening of affected patients for
abnormal serum thyroid hormone levels and subsequently for mutations in the
transporters and deiodinases.

Two blood samples will be taken during the annual venapuncture, which is
usually performed in these patients. A potential, but minor risk of
venapuncture may be a bruise or (small) hematoma.