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Protein homeostasis in the cell is achieved through highly coordinated processes including protein synthesis, folding, post-translational modifications, and transport. The endoplasmic reticulum (ER) is the central organelle where protein folding takes place and is subsequently regulated. Accumulation of unfolded proteins in ER triggers intracellular signal transduction pathways, cumulatively known as the unfolded protein response (UPR) pathway, and leads to degradation of misfolded proteins.1 The UPR is a highly conserved signal transduction system which consists of three major branches mediated by the stress sensors IRE1α, PERK, and ATF6, respectively. These branches work either cooperatively or independently and regulate downstream gene expression in order to cope with the fluctuating protein folding load in the ER.1 Despite the general roles played by the UPR pathway components, only three of them have so far been associated with human Mendelian disorders, and these include EIF2AK3,2 WFS13 and SIL1.4 As expected, mutations in these genes lead to syndromic abnormalities in human patients that involve multiple organs or systems including skeleton, brain, liver, eye, and others.2–4 In contrast, human disease correlations remain largely unknown for the remaining UPR pathway components, including 1 of the 3 core mediators, ATF6. ATF6 encodes a transmembrane protein first identified as an ER stress response element-binding factor.5 As one of the key signaling mediators activated by ER stress, ATF6 localizes on the ER membrane at the normal state. When cells undergo ER stress, ATF6 senses the signals and translocates to Golgi body where it is processed by the proteases S1P and S2P to release its cytoplasmic fragment ATF6f.1 ATF6f then induces upregulation of genes involved in ER-associated degradation to buffer ER stress and protect the cell from apoptosis.1 Surprisingly, although it plays an essential role as an ER stress sensor, ATF6 deficiency in mice shows no gross developmental abnormalities.6,7 This observation raises the possibility that mutations in ATF6 might lead to more subtle non-syndromic defects, possibly due to functional compensation by other UPR branches. Interestingly, a recent study showed that selective activation of ATF6 can help ameliorate the protein folding stress caused by mislocalized rhodopsin (RHO), a photoreceptor-specific protein,8 suggesting that ATF6 might play an important role in retina and photoreceptor survival. One of the most common genetic disorders representing photoreceptor degeneration (PRD) is retinitis pigmentosa (RP; Mendelian Inheritance in Man [MIM]# 268000; OMIM database).9 Its prevalence is approximately 1 in 3000 to 7000.9 The genetic cause of RP is highly complicated, with at least 74 RP-causing genes identified (Retinal Information Network).10 However, mutations in known RP-causing genes account for only 60% of RP cases, indicating novel loci have yet to be discovered.11 In this study, we identified ATF6 loss-of-function (LOF) mutations in a patient diagnosed with early onset PRD. These findings provide the first link between a UPR pathway gene and a human retinal genetic disorder.