The human THRB thyroid hormone receptor gene and the puzzle of retinal disease phenotypes

The THRB thyroid hormone receptor gene has attracted growing attention for its role in retinal development and disease. This gene has particularly critical roles in cone photoreceptors, the specialized cells that mediate color vision and high acuity vision. THRB controls the diversity of cone types that are required for color vision and influences cone survival in mammalian model species and human retinal organoid cultures. This central role of THRB in the cone life history prompts an expectation of equally critical roles in the human retina in vivo. Puzzlingly, overt retinal phenotypes have gone unnoticed for most known human THRB mutations. However, upon closer inspection, retinal impairment is now increasingly recognized. Mutations in 3’-exons of THRB (encoding the receptor ligand-binding domain) are known in resistance to thyroid hormone, typically a dominant syndrome with endocrine and other impairments but generally without mention of retinal disorders. However, a few specific investigations have revealed variable, usually moderate cone impairment. Recently, non-syndromic macular dystrophy cases have been found with sequence variants in a THRB 5’-exon encoding the N-terminus of one of the receptor isoforms expressed by the gene, suggesting a surprisingly wider involvement in retinal disease. We discuss this intriguing receptor gene and its emerging role in human retinal disorders. • Thyroid hormone receptors encoded by the THRB gene play a central role in the differentiation and maintenance of cone photoreceptors, the light-sensitive cell types that mediate color vision and high acuity vision. • The THRB gene has a complex structure and differentially expresses TRβ2 and TRβ1 receptor isoforms in dynamic, cell-specific patterns during retinal development. • Mutations and sequence variants in the human THRB gene are now increasingly recognized in retinal disorders, including color visual impairment, loss of high acuity vision and macular dystrophy.