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Backgrounds <p>Early-onset high myopia (EoHM) is a severe refractive error that can result in significant vision loss. A known genetic cause involves mutations in the X-linked Arrestin-3 (<i>ARR3</i>) gene, which typically presents with a female-limited inheritance pattern, in which asymptomatic fathers transmit the variant to their affected daughters.</p> Objective <p>This study aims to present a unique case of EoHM characterized by paternal transmission of a novel <i>ARR3</i> variant and to explore potential underlying molecular mechanisms through an exploratory bioinformatic analysis.</p> Methods <p>We collected the clinical phenotypes for the family and sequenced the blood using NGS and Sanger sequencing. Bioinformatic analysis of the GSE5338 dataset revealed a potential interaction network involving <i>ARR3</i>, <i>NR2E3</i> (a photoreceptor development regulator), and <i>OPN1MW</i> (a cone opsin gene).</p> Results <p>The proband exhibited severe EoHM with stretched axial lengths (ALs) (24.09 and 24.43&#xa0;mm) and pronounced myopic astigmatism. The asymptomatic father passed on a new nonsense variation in the ARR3 gene, c.7A &gt; T (p.K3Ter). Exploratory bioinformatic analysis of a murine retinal dataset hinted at a possible regulatory relationship, wherein overexpression of the photoreceptor transcription factor <i>Nr2e3</i> might be linked to the downregulation of <i>Arr3</i> and the cone opsin gene <i>Opn1mw</i>.</p> Conclusions <p>This study reports a novel <i>ARR3</i> mutation within a family affected by EoHM, expanding the known mutational spectrum of this disease and offering vital insights for genetic counseling. Furthermore, our bioinformatic analysis has generated a hypothesis that NR2E3-mediated downregulation of both ARR3 and OPN1MW may contribute to the disease phenotype, a link that warrants future investigation in human models.</p>

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Identification of a novel nonsense variant in ARR3 in a family with early-onset high myopia

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Jiahe Yu,
  • Jie Zhang,
  • Yaqin Jiang,
  • Chunli Ma,
  • Wenjing Wang,
  • Kaihui Zhang,
  • Rujin Tian,
  • Haisu Chen,
  • Haitao Han,
  • Huixin Sun,
  • Chuanzhi Peng,
  • Han Zhang,
  • Xinyan Xu

摘要

Backgrounds

Early-onset high myopia (EoHM) is a severe refractive error that can result in significant vision loss. A known genetic cause involves mutations in the X-linked Arrestin-3 (ARR3) gene, which typically presents with a female-limited inheritance pattern, in which asymptomatic fathers transmit the variant to their affected daughters.

Objective

This study aims to present a unique case of EoHM characterized by paternal transmission of a novel ARR3 variant and to explore potential underlying molecular mechanisms through an exploratory bioinformatic analysis.

Methods

We collected the clinical phenotypes for the family and sequenced the blood using NGS and Sanger sequencing. Bioinformatic analysis of the GSE5338 dataset revealed a potential interaction network involving ARR3, NR2E3 (a photoreceptor development regulator), and OPN1MW (a cone opsin gene).

Results

The proband exhibited severe EoHM with stretched axial lengths (ALs) (24.09 and 24.43 mm) and pronounced myopic astigmatism. The asymptomatic father passed on a new nonsense variation in the ARR3 gene, c.7A > T (p.K3Ter). Exploratory bioinformatic analysis of a murine retinal dataset hinted at a possible regulatory relationship, wherein overexpression of the photoreceptor transcription factor Nr2e3 might be linked to the downregulation of Arr3 and the cone opsin gene Opn1mw.

Conclusions

This study reports a novel ARR3 mutation within a family affected by EoHM, expanding the known mutational spectrum of this disease and offering vital insights for genetic counseling. Furthermore, our bioinformatic analysis has generated a hypothesis that NR2E3-mediated downregulation of both ARR3 and OPN1MW may contribute to the disease phenotype, a link that warrants future investigation in human models.