Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene

Kacie J Meyer; John H Fingert; Michael G Anderson

doi:10.1093/hmg/ddae088

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Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene

Journal article

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Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene

Kacie J Meyer, John H Fingert and Michael G Anderson

Human molecular genetics, Vol.33(17), pp.1481-1494

09/01/2024

DOI: 10.1093/hmg/ddae088

PMCID: PMC13142156

PMID: 38770563

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Abstract

Exfoliation syndrome (XFS) is a systemic disease of elastin-rich tissues involving a deposition of fibrillar exfoliative material (XFM) in the anterior chamber of the eye, which can promote glaucoma. The purpose of this study was to create mice with CRISPR/Cas9-induced variations in candidate genes identified from human genome-wide association studies (GWAS) and screen them for indices of XFS. Variants predicted to be deleterious were sought in the Agpat1, Cacna1a, Loxl1, Pomp, Rbms3, Sema6a, and Tlcd5 genes of C57BL/6J mice using CRISPR/Cas9-based gene editing. Strains were phenotyped by slit-lamp, SD-OCT imaging, and fundus exams at 1-5 mos of age. Smaller cohorts of 12-mos-old mice were also studied. Deleterious variants were identified in six targets; Pomp was recalcitrant to targeting. Multiple alleles of some targets were isolated, yielding 12 strains. Across all genotypes and ages, 277 mice were assessed by 902 slit-lamp exams, 928 SD-OCT exams, and 358 fundus exams. Homozygosity for Agpat1 or Cacna1a mutations led to early lethality; homozygosity for Loxl1 mutations led to pelvic organ prolapse, preventing aging. Loxl1 homozygotes exhibited a conjunctival phenotype of potential relevance to XFS. Multiple other genotype-specific phenotypes were variously identified. XFM was not observed in any mice. This study did not detect XFM in any of the strains. This may have been due to species-specific differences, background dependence, or insufficient aging. Alternatively, it is possible that the current candidates, selected based on proximity to GWAS signals, are not effectors acting via monogenic loss-of-function mechanisms.

exfoliation syndrome

GWAS

mouse model

fibrillar exfoliative material

ocular

UIOWA OA Agreement

Details

Title: Subtitle: Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene
Creators: Kacie J Meyer - University of Iowa
John H Fingert - University of Iowa
Michael G Anderson - University of Iowa
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.33(17), pp.1481-1494
DOI: 10.1093/hmg/ddae088
PMID: 38770563
PMCID: PMC13142156
NLM abbreviation: Hum Mol Genet
eISSN: 1460-2083
Publisher: Oxford University Press
Grant note: Glaucoma Foundation Research to Prevent Blindness Roy J. and Lucille A. Carver College of Medicine P30EY025580 / National Institutes of Health Center Support to the University of Iowa R21EY029991 / NIH HHS Hadley-Carver Chair in Glaucoma
Language: English
Electronic publication date: 05/20/2024
Date published: 09/01/2024
Academic Unit: Molecular Physiology and Biophysics; Ophthalmology and Visual Sciences
Record Identifier: 9984628051802771

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