Background: Congenital, isolated, central, hypothyroidism (CCH), is rare and evades diagnosis on TSH-based congenital hypothyroidism screening programmes in the UK. Genetic ascertainment is therefore paramount in enabling prompt diagnosis and treatment of familial cases. Recognised causes include TSHB and IGSF1 gene defects, with only two previous reports of biallelic, highly disruptive (nonsense; R17X, in-frame deletion and missense; p.S115-T117del+T118), mutations in the TRHR gene. Here, we describe the first homozygous missense mutation in TRHR, associated with a typical phenotype.
Case: A female infant from a consanguineous Pakistani family, presented with prolonged neonatal jaundice and was found to have central hypothyroidism (TSH 2.2 mU/l, NR 0.43.5 and free T4 7.9 pmol/l, NR 10.721.8), with otherwise normal pituitary function. With TSHB or IGSF1 mutations being usually associated with profound or X-linked CCH, a TRHR mutation was sought.
Results: Sequencing identified a homozygous mutation (P81R) in TRHR, substituting arginine for a proline residue in transmembrane helix 2 (TM2) which is highly conserved amongst G-protein coupled receptors (GPCRs). Functional studies showed that although the mutant receptor was expressed and localised to the cell membrane normally, its ability to bind radiolabelled TRH and signal via Gqα was markedly impaired, likely due to disruption of structure of TM2.
Conclusion: We describe the first deleterious, missense TRHR defect associated with moderate CCH. Importantly, the location of the mutated amino acid (proline 81) highlights a previously unanticipated functional importance of the TM2 in mediating hormone binding and receptor activation. Future identification of other, naturally-occurring, TRHR mutations may map the molecular basis of ligand binding and activation of TRHR which are poorly understood.