Characterizing the Impact of a Novel LRP5 Splicing Variant (c.4488+T>G) on Protein Structure and FEVR Pathogenesis

Authors

Emily Jagenburg, Oakland University William Beaumont School of Medicine Medical Student
Savyo Kirkor
Christopher Alexopoulos
Wendy A. Dailey
Kimberly Drenser, Corewell Health East
Kenneth P. Mitton

Document Type

Conference Proceeding

Publication Date

6-2025

Publication Title

Investigative Ophthalmology and Visual Science

Abstract

Purpose : To analyze the impact of splice site and nonsense variations in LRP5 on protein structure using AlphaFold-3, with emphasis on novel splice donor variant identified in an 11-person cohort

Methods : Participants were consented under IRB approval for providing samples to the Associated Retinal Consultants (ARC) Eye Biobank and for the targeted sequencing DNA analysis in the Eye Research Institute. Genomic DNA was extracted and prepared for Illumina AmpliSeq targeted sequencing on the Illumina iSeq-100. A custom panel included 7 FEVR-associated genes spanning 83 exons with 25 bp intron padding. Variants were analyzed using the Ensembl Variant Effect Predictor Database, with pathogenicity assessed via ClinVar. Likely pathogenic variants of LRP5 (e.g., c.4488+T>G) were modeled using AlphaFold-3.1,3

Results : Among 11 samples, 3 patients carried the novel splice donor variant in 5’ end of intron-21 in LRP5 (c.4488+T>G), replacing the last 118 amino acids with 61 nonsense amino acids. One of these patients also harbored a duplication LRP5 variant (Leu20dup), while another carried a missense FZD4 variant (Pro11Gln). Another family exhibited common LRP5 missense variants (Val667Met, Ala1330Val), with only 2 out of 5 members showing clinically significant FEVR.1,4 Two female patients had a LRP5 deletion (Leu16_Leu20del) and ZNF408 deletion (Val194_Val197del); One of the two subjects had grade 1 FEVR. Patients with missense variants (Val667Met, Ala1330Val) displayed FEVR grades 4 and 5. The LRP5 (c.4488+T>G) splice donor predicted by AlphaFold-3 significantly changes the structure of the intracellular domain, truncating the c-terminal domain.

Conclusions : The novel splice donor variant (c.4488+T>G) in LRP5 disrupts the intracellular domain, indicating the pathogenicity. However, multifactorial influences may exacerbate disease severity, as seen in the proband with an additional FZD4 missense variant (Pro11Gln) and FEVR Grade 5. Deletions in LRP5 (Leu16_Leu20del) and ZNF408 deletion (Val194_Val197del) appear benign or of uncertain significance, reinforcing the complexity of FEVR pathogenesis. These findings suggest interplay of genetic and environmental factors in FEVR, and future studies may explore this further.

Volume

66

Issue

8

First Page

1823

Comments

Association for Research in Vision and Ophthalmology ARVO Annual Meeting, May 4-8, 2025, Salt Lake City, UT

Last Page

1823

Recommended Citation

Jagenburg E, Kirkor S, Alexopoulos C, Dailey WA, Drenser K, Mitton KP. Characterizing the impact of a novel LRP5 splicing variant (c.4488+T>G) on protein structure and FEVR pathogenesis. Invest Ophthal Vis Sci. 2025 Jun;66(8):1823.