Mutations in thyroid hormone receptor alpha 2

Thyroid hormone is crucial for normal development and metabolism and acts
mainly via its nuclear receptors. The function of the T3 binding receptor
isoforms is well understood. In contrast, TRa2 does not bind T3, despite
representing a true isoform. The biological role of TRa2 is not understood. We
identified a nonsense mutation in the THRA gene resulting in a premature stop
of TRa2 in two related subjects. This family provides a unique possibility in
investigating the biological function of TRa2 and pathophysiological
consequences of this TRa2 premature stop. We hypothesize that TRα2 is an
orphan receptor with an important role in specific signaling pathways and that
mutations in TRα2 have pathophysiological consequences.

The family with the TRα2 premature stop enables us to investigate the
biological role of the orphan wild-type TRα2 and the consequences of its
dysfunction. The primary objectives of this proposal are (i) to search for a
biological function of TRα2 and (ii) to investigate if the function of TRα2 is
abrogated in the patients with mutations in TRα2.

Observational study.

Venous blood samples will be take from fasted subjects. In total, approximately
15 cc blood will be drawn (5 ml for DNA extraction and 10 ml for serum
measurements). Skin biopsies of the forearm will be taken using
well-established techniques. Blood samples as well as skin biopsies are both
regarded as minimal invasive procedures. Since the function of TRα2 is unknown,
possible benefits are currently unclear. The discovery of a family with a
mutant TRa2 provides the unique opportunity to investigate the pathophysiologic
consequences of disrupted TRa2 signaling.