Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa.

Laura Kuehlewein,Ditta Zobor,Karin Schäferhoff,Susanne Kohl,Pascale Mazzola,Nicole Weisschuh,Saskia Biskup,Muhammad Imran Khan,Frans P.M Cremers,Fadi Nasser,Antje Bernd,Melanie Kempf,Tobias B Haack,Katarina Stingl,Tilman Heinrich,Bernd Wissinger,Eberhart Zrenner

doi:10.3390/ijms22052374

Abstract

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

Highlights

Retinitis pigmentosa (RP) is a hereditary degenerative retinal disease that causes severe visual impairment and vision loss due to the progressive degeneration of, primarily, the rod and, secondarily, the cone photoreceptors
First (n = 16) or second (n = 5) decades of life. One patient reported her first symptoms during her third decade of life (SRP759-19456)
We reported 24 patients from 21 families with retinitis pigmentosa (RP) caused by likely path- 87 ogenic and biallelic variants in the PDE6B gene

Summary

Introduction

Retinitis pigmentosa (RP) is a hereditary degenerative retinal disease that causes severe visual impairment and vision loss due to the progressive degeneration of, primarily, the rod and, secondarily, the cone photoreceptors (i.e., rod–cone dystrophy). The rod photoreceptor cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6) plays a crucial role in vertebrate phototransduction. PDE comprises four subunits: one catalytic alpha-subunit PDE6A, one catalytic betasubunit PDE6B, and two inhibitory gamma-subunits PDE6G. The gene encoding the beta subunit of PDE6 (PDE6B) was one of the first genes identified as causing retinal degeneration in mice, dogs, and humans (i.e., autosomal-recessive RP and autosomal-dominant stationary night blindness) [2,3,4,5,6,7,8,9,10,11]. The gene is located on chromosome 4p16.3 (OMIM *180072) and comprises 22 coding exons and encodes 854 amino acid residues [12]

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