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Abstract Background Myopia-26, a Mendelian form of early-onset high-myopia (eoHM) caused by mutations in the X-chromosomal ARR3 gene and predominantly affecting females, curiously, may provide an alternative route of investigation to unveil retinal mechanisms underlying pathological eye growth. We conducted a case-control cross-sectional prospective electrophysiological study in genetically characterized Myopia-26 patients (ARR3 heterozygous symptomatic females) compared with high myopes harboring intact ARR3 alleles and one carrier hemizygous male. Results Participants were 26 volunteers: 10 healthy control females (E-CTRL, mean age = 31.5 ± 8.8 years), one healthy control male, one carrier male of the mutant ARR3 allele and 14 female eoHM patients (mean age = 27.0 ± 13.1 years) divided in two groups: seven without (M-CTRL) and seven with (MYP-26) genetic alteration in the ARR3 gene. The clinical evaluation included complete eye screening and full-field electroretinograms (ERGs) recorded from both eyes under mydriasis. Spherical equivalent was comparable (mean=-9.55 ± 2.46 and − 10.25 ± 3.22 for M-CTRL and MYP-26, respectively) and best corrected visual acuity (BCVA) was significantly different between M-CTRL and MYP-26 (1.0 vs. 0.406 ± 0.253, respectively). E-CTRL and M-CTRL showed similar light-adapted flash and flicker ERG amplitudes; however, the prior values were reduced by ~ 35% (a- and b-waves alike), the latter by ~ 55% in the MYP-26 group (F(2, 45) > 21.821, p

Background: Myopia-26, a Mendelian form of early-onset high-myopia (eoHM) caused by mutations in the X-chromosomal ARR3 gene and predominantly affecting females, curiously, may provide an alternative route of investigation to unveil retinal mechanisms underlying pathological eye growth. We conducted a case-control cross-sectional prospective electrophysiological study in genetically characterized Myopia-26 patients (ARR3 heterozygous symptomatic females) compared with high myopes harboring intact ARR3 alleles and one carrier hemizygous male. Results: Participants were 26 volunteers: 10 healthy control females (E-CTRL, mean age = 31.5 ± 8.8 years), one healthy control male, one carrier male of the mutant ARR3 allele and 14 female eoHM patients (mean age = 27.0 ± 13.1 years) divided in two groups: seven without (M-CTRL) and seven with (MYP-26) genetic alteration in the ARR3 gene. The clinical evaluation included complete eye screening and full-field electroretinograms (ERGs) recorded from both eyes under mydriasis. Spherical equivalent was comparable (mean=-9.55 ± 2.46 and − 10.25 ± 3.22 for M-CTRL and MYP-26, respectively) and best corrected visual acuity (BCVA) was significantly different between M-CTRL and MYP-26 (1.0 vs. 0.406 ± 0.253, respectively). E-CTRL and M-CTRL showed similar light-adapted flash and flicker ERG amplitudes; however, the prior values were reduced by ~ 35% (a- and b-waves alike), the latter by ~ 55% in the MYP-26 group (F(2, 45) > 21.821, p < 0.00001). Dark-adapted a-wave amplitudes were slightly reduced (by ~ 20%) in all myopic patients compared to E-CTRL, irrespective of the ARR3 genotype (E-CTRL vs. eoHM, p = 0.038). Conclusions: The cone dysfunction observed in Myopia-26 patients is specifically linked to the mutation of ARR3, and is not the consequence of eoHM, i.e. elongation of the eye. It may play a role in myopic refractive error development through a yet unconfirmed pathomechanism. [ABSTRACT FROM AUTHOR]

X-linked myopia 26 (Myopia 26, MIM #301010), which is caused by the variants of ARR3 (MIM *301770), is characterized by female-limited early-onset high myopia (eo-HM). Clinical characteristics include a tigroid appearance in the fundus and a temporal crescent of the optic nerve head. At present, the limited literature on eo-HM caused by ARR3 mutations shows that its inheritance mode is complex, which brings certain difficulties to pre-pregnancy genetic counseling, pre-implantation genetic diagnosis, and prenatal diagnosis. Here, we investigated the genetic underpinning of a Chinese family with eo-HM. Whole exome sequencing of the proband revealed a novel frameshift mutation in ARR3 (NM_004312, exon10, c.666delC, p. Asn222LysfsTer22). Although the mode of inheritance of the eo-HM family fits the X-linked pattern of ARR3, the phenotypes of three patients deviate from the typical early-onset high myopia. Through X-chromosome inactivation experiments, the patient's different phenotypes can be precisely explained. In addition, this study not only enhanced the correlation between ARR3 and early-onset high myopia but also provided explanations for different phenotypes, which may inspire follow-up studies. Our results enrich the knowledge of the variant spectrum in ARR3 and provide critical information for preimplantation and prenatal genetic testing, diagnosis, and counseling. [ABSTRACT FROM AUTHOR]

Arrestins are key molecules involved in the signaling of light-sensation initiated by visual pigments in retinal photoreceptor cells. Vertebrate photoreceptor cells have two types of arrestins, rod arrestin, which is encoded by SAG and is expressed in both rods and cones, and cone arrestin, encoded by ARR3 in cones. The arrestins can bind to visual pigments, and thus regulate either dim-light vision via interactions with rhodopsin or bright-light vision together with cone visual pigments. After adapting to terrestrial life, several amniote lineages independently went back to the sea and evolved deep-diving habits. Interestingly, the rhodopsins in these species exhibit specialized phenotypes responding to rapidly changing dim-light environments. However, little is known about whether their rod arrestin also experienced adaptive evolution associated with rhodopsin. Here, we collected SAG coding sequences from >250 amniote species, and examined changes in selective pressure experienced by the sequences from deep-diving taxa. Divergent patterns of evolution of SAG were observed in the penguin, pinniped and cetacean clades, suggesting possible co-adaptation with rhodopsin. After verifying pseudogenes, the same analyses were performed for cone arrestin (ARR3) in deep-diving species and only sequences from cetacean species, and not pinnipeds or penguins, have experienced changed selection pressure compared to other species. Taken together, this evidence for changes in selective pressures acting upon arrestin genes strengthens the suggestion that rapid dim-light adaptation for deep-diving amniotes require SAG, but not ARR3.

ARR3 has been associated with X-linked, female-limited, high myopia. However, using exome sequencing (ES), we identified the first high myopia case with hemizygous ARR3-related mutation in a male patient in a Southern Chinese family. This novel truncated mutation (ARR3: c.569C>G, p.S190*) co-segregated with the disease phenotype in affected family members and demonstrated that high myopia caused by ARR3 is not X-linked, female-limited, where a complicated X-linked inheritance pattern may exist. Thus, our case expanded the variant spectrum in ARR3 and provided additional information for genetic counseling, prenatal testing, and diagnosis. Moreover, we characterized the nonsense-mediated decay of the ARR3 mutant mRNA and discussed the possible underlying pathogenic mechanisms.

ARR3 has been associated with X-linked, female-limited, high myopia. However, using exome sequencing (ES), we identified the first high myopia case with hemizygous ARR3 -related mutation in a male patient in a Southern Chinese family. This novel truncated mutation (ARR3 : c.569C>G, p.S190*) co-segregated with the disease phenotype in affected family members and demonstrated that high myopia caused by ARR3 is not X-linked, female-limited, where a complicated X-linked inheritance pattern may exist. Thus, our case expanded the variant spectrum in ARR3 and provided additional information for genetic counseling, prenatal testing, and diagnosis. Moreover, we characterized the nonsense-mediated decay of the ARR3 mutant mRNA and discussed the possible underlying pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Background: Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis.Results: We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation.Conclusions: This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease. [ABSTRACT FROM AUTHOR]

Purpose: To detect variants in 17 known potentially causative genes for non‐syndromic myopia in 67 Tujia Chinese patients with early‐onset high myopia (eo‐HM). Methods: DNA from 67 unrelated patients with early onset (<7 years old) high myopia (refraction error ≤ −6.00D or axial length > 26 mm) were subjected to whole‐exome sequencing (WES). Variants in 17 candidate genes were analysed by multistep bioinformatics analysis. Subsequently, Sanger sequencing was used to verify identified candidate mutations and to assess available family members for co‐segregation with myopia. Results: A multistep systematic analysis of variants in 17 potentially causative genes for eo‐HM revealed four novel pathogenic mutations and three potential pathogenic mutations in 4 of 17 genes in 7 of 67 (10.4%) probands. The pathogenic group included one missense mutation (c.100G > C, p.Asp34His) and one splice donor mutation (c.989 + 1G >A) in ARR3, one missense mutation (c.995C > A, p.Thr332Lys) in NDUFAF7 and one novel frameshift mutation (c.726dupA, p.Arg243fs*140) in SLC39A5. The potential pathogenic group included two missense mutations (c.3266A > G, p.Tyr1089Cys; c.913G > A, p.Glu305Lys) in ZNF644 and one missense mutation (c.960T > A, p.His320Gln) in NDUFAF7. Sequence changes were confirmed by Sanger sequencing; all had an allele frequency <0.01 in the 1000G, EVS, ExAC and gnomAD databases. Additionally, both the pathogenic and potentially pathogenic mutations were predicted to be damaging by SIFT, Polyphen‐2, PROVEAN, MutationTaster2, CADD and REVEL except the p.Tyr1089Cys and p.Glu305Lys changes were predicted to be neutral by PROVEAN. Conclusion: Our research provides more evidence to support the hypothesis that mutations in ARR3, SLC39A5 and NDUFAF7 are disease‐causing genes for eo‐HM and broadens the eo‐HM mutation spectrum among different ethnic groups. It also deepens understanding of the contributions of ARR3, SLC39A5, and NDUFAF7 to eo‐HM. [ABSTRACT FROM AUTHOR]

Arsenic is one of the most prevalent toxic elements in the environment, and its toxicity affects every organism. Arsenic resistance has mainly been observed in microorganisms, and, in bacteria, it has been associated with the presence of the Ars operon. In Saccharomyces cerevisiae , three genes confer arsenic resistance: ARR1 , ARR2 , and ARR3 . Unlike bacteria, in which the presence of the Ars genes confers per se resistance to arsenic, most of the S. cerevisiae isolates present the three ARR genes, regardless of whether the strain is resistant or sensitive to arsenic. To assess the genetic features that make natural S. cerevisiae strains resistant to arsenic, we used a combination of comparative genomic hybridization, whole-genome sequencing, and transcriptomics profiling with microarray analyses. We observed that both the presence and the genomic location of multiple copies of the whole cluster of ARR genes were central to the escape from subtelomeric silencing and the acquisition of resistance to arsenic. As a result of the repositioning, the ARR genes were expressed even in the absence of arsenic. In addition to their relevance in improving our understanding of the mechanism of arsenic resistance in yeast, these results provide evidence for a new cluster of functionally related genes that are independently duplicated and translocated.