The Presence of Wnt Signaling Mutations in Patients With Diabetic Retinopathy

Abstract

Purpose: The relationship between poor hemoglobin A1c (HbA1c) control and risk of proliferative diabetic retinopathy (PDR) is well known. Nevertheless, some patients have discordant disease (controlled HbA1c and severe PDR or vice versa). One potential explanation for this discrepancy is the presence of underlying genetic mutations in the Wingless-related integration site (Wnt) signaling pathway. However, minimal clinical data exist on the presence of Wnt signaling mutations in patients with diabetes mellitus (DM) and the correlation with diabetic retinopathy.

Methods: Retrospective, nonconsecutive case review of patients with type 1 or 2 DM who underwent genetic testing for at least 1 recognized Wnt signaling pathway mutation from 2011 to 2016. The clinical course and retinal images were reviewed for patients with identifiable mutations.

Results: Thirty-six patients, ages 13 to 79 years, consented for genetic analysis. Three patients (8.3%) exhibited at least 1 recognized genetic mutation in the Wnt signaling pathway. Case 1 was a 65-year-old female with type 1 diabetes for > 20 years, HbA1c <7.0%, and no findings of diabetic retinopathy (Tetraspanin 12). Case 2 was a 13-year-old male with type 1 diabetes for 8 years, moderate HbA1c control (7.6-8.3%), and absence of diabetic retinopathy (Norrin). Case 3 was a 48-year-old male with severe PDR requiring multiple laser and antivascular endothelial growth factor (anti-VEGF) treatments despite well-controlled HbA1c (6.0%) (Frizzled-4).

Conclusion: Wnt signaling pathway mutations exist in patients with DM. Further studies investigating the prevalence and clinical significance of these mutations in a larger diabetic population are warranted. Identification of these patients with genetic testing may enable earlier medical intervention.

Keywords: HbA1c; Wnt signaling; diabetes mellitus; diabetic retinopathy; precision medicine.

Figure 1.

Case 1. Baseline fundus photography and fluorescein angiography, and schematic diagram of Tetraspanin 12 (TSPAN12). Fundus photographs of the (A) right and (B) left eyes demonstrating normal retinal periphery without neovascularization, exudates, hemorrhage, or fluid. Early-phase fluorescein angiography (FA) of the (C) right eye and mid-phase FA of the (D) left and (E) right eyes are unremarkable. (F) Schematic diagram of TSPAN12 illustrating previously identified mutations in patients with Wingless-related integration site-associated vitreoretinopathies, as well as the novel mutation identified in this study.

Figure 2.

Case 2. Fundus photography, fluorescein angiography, and optical coherence tomography (OCT) at baseline, and schematic diagram of Norrin. Normal fundus photographs of the (A) right and (B) left eyes with the exception of minimal retinal pigment changes noted bilaterally. (C) Unremarkable early-phase angiography of the right eye, and late-phase angiography of the (D) left and (E) right eyes. OCT of the (F) left and (G) right eyes demonstrating normal retinal contour without macular edema or subretinal fluid. (H) Schematic diagram of Norrin (NDP) illustrating the trio of disulfide bonds between 6 cysteine residues (boxes) which give rise to the highly conserved cystine knot motif essential for forming the Frizzled-4 receptor binding site, NDP dimerization, and downstream activation of the Wnt signaling pathway. In patients with Wnt-associated vitreoretinopathies, mutations outside these critical domains result in milder phenotypes.

Figure 3.

Case 3. Fundus photography, fluorescein angiography, and optical coherence tomography (OCT) at baseline, and schematic diagram of the Frizzled-4 (FZD4) amino acid sequence. Fundus photographs of the (A) right and (B) left eyes demonstrate arteriovenous nicking and focal laser scarring. (C) Early-phase fluorescein angiography of the right eye. Mid-phase fluorescein angiography of the (D) left and (E) right eyes, along with (F) late-phase angiography of the left eye demonstrate hyperfluorescence consistent with leakage. Macular edema noted on OCT of the (G) right and (H) left eyes. (I) Schematic diagram of the FZD4 amino acid sequence illustrating the N-terminus cysteine-rich motif which binds to Norrin, the motifs for downstream activation of the canonical and conventional Wingless-related integration site signaling pathways, and the L256 V mutation located in the first of 7 transmembrane domains (asterisk) identified in this study. AA, amino acid; JNK, C-Jun N-terminal kinase; SS, Splice site.

Figure 4.

Case 3. Fundus photographs, fluorescein angiography, and optical coherence tomography (OCT) at 4-year follow-up. Fundus photographs of the (A) right and (B) left eyes show scarring from focal laser treatments. Early-phase fluorescein angiography of the (C) right eye and (D) left eye. Decreased hyperfluorescence noted on late-phase angiography of the (E) right and (F) left eyes indicative of decreasing leakage. (G and H) OCT of the right and left eyes demonstrates worsening macular edema.