Background: To document an infant with a cone photoreceptor disorder associated with severe thyroid hormone resistance due to compound heterozygosity in the thyroid hormone receptor beta 2 (TRβ2) encoding gene THRβ2.
Materials and methods: Cone photoreceptor function was assessed using standard electroretinography (ERG) including colored flashes. We PCR-amplified and sequenced exons 8-10 of the THRβ2 gene. We cloned and sequenced a genomic segment (exons 9-10) of the THRβ2 gene to confirm a compound heterozygote mutation. We investigated whether mutations in the (OPN1LW-OPN1MW) gene array were responsible for the phenotype.
Results: ERG testing showed a normal scotopic response and severely reduced photopic response. Spectral testing showed a small amplitude b-wave to a red flash and a larger amplitude b-wave to the blue flash. Molecular analysis revealed this child was a compound heterozygote for p.R338W and p.R429W mutations in exons 9 and 10 of the THRβ2 gene. These two mutations lie within the ligand-binding domain that is known to selectively inhibit Trβ2 binding as homodimers to the thyroid hormone receptor response elements (TREs). No mutations were found within the OPN1LW and OPN1MW genes or the locus control region that regulates expression of these opsin genes.
Conclusion: We document a congenital disorder of cone function characterized by severely reduced L- and M-cone responses and increased S-cone responses caused by deleterious mutations in the THRβ2 gene in thyroid resistant patients. Thyroid hormone, via TRβ2, is critical for determining cone-type differentiation in humans.