Purpose: To investigate the function and pathogenicity of HRG4, a photoreceptor synaptic protein homologous to the Caenorhabditis elegans neuroprotein UNC119.
Methods: HRG4 was screened for mutations in patients with various retinopathies, and a transgenic mouse model was constructed and analyzed based on a mutation found.
Results: A heterozygous premature termination codon mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy. In some transgenic mice carrying the identical mutation, age-dependent fundus lesions developed accompanied by electroretinographic changes consistent with defects in photoreceptor synaptic transmission (depressed b-wave, normal c-wave), and retinal degeneration occurred with marked synaptic and possible transsynaptic degeneration.
Conclusions: HRG4, the only synaptic protein known to be highly enriched in photoreceptor ribbon synapses, is now shown to be pathogenic when mutated.