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.