Investigative Ophthalmology & Visual Science Cover Image for Volume 65, Issue 7
June 2024
Volume 65, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2024
RNA Polymerase II Associated Protein 3 (RPAP3), a novel candidate gene for normal-tension glaucoma
Author Affiliations & Notes
  • William Presley
    Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
  • Sarah Garnai
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Bin Guan
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Sayoko E Moroi
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
    Department of Ophthalmology and Visual Sciences, The Ohio State University, Columbus, Ohio, United States
  • Natalie Michaels
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Bridget Blevins
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Brenda Bohnsack
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
    Department of Ophthalmology, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Jill A Rosenfeld
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Richard A Lewis
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
    Undiagnosed Diseases Network, Massachusetts, United States
  • Lindsay Burrage
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Shamika Ketkar
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
  • Seong H Jeong
    Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
  • Robert Hufnagel
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Julia E Richards
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Joshua D Stein
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Lev Prasov
    Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States
    Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   William Presley None; Sarah Garnai None; Bin Guan None; Sayoko Moroi None; Natalie Michaels None; Bridget Blevins None; Brenda Bohnsack None; Jill Rosenfeld None; Richard Lewis None; Lindsay Burrage None; Shamika Ketkar None; Seong Jeong None; Robert Hufnagel None; Julia Richards None; Joshua Stein None; Lev Prasov None
  • Footnotes
    Support  NH Grant 1F31EY035557-01
Investigative Ophthalmology & Visual Science June 2024, Vol.65, 4245. doi:
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    • Get Citation

      William Presley, Sarah Garnai, Bin Guan, Sayoko E Moroi, Natalie Michaels, Bridget Blevins, Brenda Bohnsack, Jill A Rosenfeld, Richard A Lewis, Lindsay Burrage, Shamika Ketkar, Seong H Jeong, Robert Hufnagel, Julia E Richards, Joshua D Stein, Lev Prasov; RNA Polymerase II Associated Protein 3 (RPAP3), a novel candidate gene for normal-tension glaucoma. Invest. Ophthalmol. Vis. Sci. 2024;65(7):4245.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Normal-tension (normal-pressure) glaucoma (NTG) is a characteristic optic neuropathy with clinically measured intraocular pressure (IOP) in the 8-21 mmHg range. A small subset of these patients show progression despite successful IOP-lowering treatment, supporting the need for genetic studies into NTG pathogenesis and novel therapeutic targets. To that end, we report on a large family presenting with severe, early-onset (ages 35-55) NTG.

Methods : Linkage analysis was conducted on 13 family members (11 affected, 2 unaffected) via an IlluminaQC SNP array, and max logarithm of the odds (LOD) scores were calculated using an autosomal dominant, fully penetrant model with disease frequency at 1%. Exome and whole genome sequencing were also performed and resulting variants prioritized by familial/population allele frequencies and segregation, in silico pathogenicity scores, and pan-eye expression. Subsequently, RNA was extracted from familial blood samples for Illumina polyA-enriched RNAseq, followed by DESeq2 differentially expressed genes (DEGs) and Gene-Ontology analyses.

Results : Genomic linkage/segregation results suggest multiple risk alleles in this family, though the majority of NTG cases map to a region on chromosome 12q13 (maxLOD = 2.6) containing the single candidate variant defined by variant prioritization, RPAP3 p.R26L (c.163 C>A). RPAP3 is a ubiquitously expressed co-chaperone protein implicated in cup-to-disc ratio by GWAS. It stimulates the ATPase activity of HSP90, which then regulates extracellular matrix (ECM) formation/maintenance through its role in TGFβ signaling. Pathway/molecular function analysis on patient DEGs revealed downregulation in ECM structural constituents (FDR 5.4 E-9); ECM, fibrinogen, fibronectin, and integrin binding (FDRs 2.3E-2, 4.3E-2, 7.5E-3, and 2E-3); and collagen metabolism (FDR 1E-2) tracking with RPAP3 variant status. We have also identified a second family with a similar NTG phenotype that carries the RPAP3 variant p.L42P.

Conclusions : These data support a role for RPAP3 in NTG pathogenesis through possible dysregulation of ECM production. Ongoing biochemical/functional studies will clarify the specific molecular mechanism and may provide a novel therapeutic target for NTG.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Plotted DEGs show TGFβ and ECM dysregulation tracking with the RPAP3 variant. A secondary diagnosis of high myopia in G04746 may explain optic atrophy despite WT status.

Plotted DEGs show TGFβ and ECM dysregulation tracking with the RPAP3 variant. A secondary diagnosis of high myopia in G04746 may explain optic atrophy despite WT status.

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