Introduction
Myopia occurs when the axial length of the eyes is too long, typically, causing distant objects to be focused in front of the retina(Young, 2009). High myopia (HM) is a common human genetic sensory defect characterized by reduced vision, retinal degeneration and choroidal atrophy. Its global prevalence exceeds 2.9%(Holden et al., 2016; Saw, 2003). HM is defined by diopters (D) greater than -6.0 or an axial length greater than 26 mm(Young, Metlapally, & Shay, 2007).
Both environmental and genetic factors can influence the severity of myopia(Morgan, Ohno-Matsui, & Saw, 2012; Saw, Katz, Schein, Chew, & Chan, 1996), with some family studies showing that genetic factors play a crucial role in the development of HM(Cai et al., 2019; Young et al., 2007). ARR4 (RefSeq NM_004312.3, see Materials and Methods, “Nomenclature”) gene is associated with X-linked, female-limited HM because in the three families examined all affected patients were female, it has recently been reported that the ARR4 gene is associated with X-linked, female-limited HM(Xiao, Li, Jia, Guo, & Zhang, 2016) . Even though several male family members were hemizygous, they did not possess the phenotypic features of HM thereby proving to be the second disease, after those associated with PCDH19 , with this unusual inheritance pattern(Depienne et al., 2009).
Accumulation of misfolded and mutant proteins disrupts cellular homeostasis, which will lead to endoplasmic reticulum (ER) stress(Hiramatsu, Chiang, Kurt, Sigurdson, & Lin, 2015). ER stress causes the activation of the unfolded protein response (UPR), which restores the homeostasis of the ER and protects cells from further damage(Walter & Ron, 2011). However, the activation of UPR hinders protein translation, and chronic stress response will cause cell apoptosis(Mendes, van der Spuy, Chapple, & Cheetham, 2005). ER stress and UPR are found to be associated with the development of various ocular diseases(Kroeger, Chiang, Felden, Nguyen, & Lin, 2019), including diabetic retinopathy(Fu et al., 2012; Li, Wang, Yu, Wang, & Zhang, 2009; Oshitari, Yoshida-Hata, & Yamamoto, 2011; Tang et al., 2011; Yan et al., 2012), glaucoma(Zode et al., 2011; Zode et al., 2014), retinal pigmentary degeneration(Lobo, Au, Kiser, & Hagstrom, 2016), and retinal dystrophy(W. C. Chiang et al., 2017; Kohl et al., 2015; Skorczyk-Werner et al., 2017) Ultimately, while protein destabilization will produce misfolded proteins and protein accumulation, proteasome and lysosomal degradation pathways play an important role in the elimination of misfolded proteins(Balchin, Hayer-Hartl, & Hartl, 2016). Previous studies have found that the UPR and cell stress caused by the pathogenic variation of Arrestin-1 are the causes of photoreceptor death (Vishnivetskiy et al., 2018)。
In this study, a member of a Chinese family was referred for HM. While funduscopy results were suggestive of a case of HM, exome sequencing (ES) revealed that an ARR4 variant which submitted to the LOVD was responsible for the phenotype. This finding is in stark contrast to previous research that has suggested that ARR4 variants associated with HM are present only in females(Xiao et al., 2016). In the family included in this study, one hemizygote male was affected, implying that ARR4 has more complicated hereditary patterns than initially thought. These results showed that the nonsense mutation ofARR4 gene led to ER stress and UPR, and then induced cell stress which may be the cause of photoreceptor apoptosis.