The Interplay between Peripherin 2 Complex Formation and Degenerative Retinal Diseases

Abstract

Peripherin 2 (Prph2) is a photoreceptor-specific tetraspanin protein present in the outer segment (OS) rims of rod and cone photoreceptors. It shares many common features with other tetraspanins, including a large intradiscal loop which contains several cysteines. This loop enables Prph2 to associate with itself to form homo-oligomers or with its homologue, rod outer segment membrane protein 1 (Rom1) to form hetero-tetramers and hetero-octamers. Mutations in PRPH2 cause a multitude of retinal diseases including autosomal dominant retinitis pigmentosa (RP) or cone dominant macular dystrophies. The importance of Prph2 for photoreceptor development, maintenance and function is underscored by the fact that its absence results in a failure to initialize OS formation in rods and formation of severely disorganized OS membranous structures in cones. Although the exact role of Rom1 has not been well studied, it has been concluded that it is not necessary for disc morphogenesis but is required for fine tuning OS disc size and structure. Pathogenic mutations in PRPH2 often result in complex and multifactorial phenotypes, involving not just photoreceptors, as has historically been reasoned, but also secondary effects on the retinal pigment epithelium (RPE) and retinal/choroidal vasculature. The ability of Prph2 to form complexes was identified as a key requirement for the development and maintenance of OS structure and function. Studies using mouse models of pathogenic Prph2 mutations established a connection between changes in complex formation and disease phenotypes. Although progress has been made in the development of therapeutic approaches for retinal diseases in general, the highly complex interplay of functions mediated by Prph2 and the precise regulation of these complexes made it difficult, thus far, to develop a suitable Prph2-specific therapy. Here we describe the latest results obtained in Prph2-associated research and how mouse models provided new insights into the pathogenesis of its related diseases. Furthermore, we give an overview on the current status of the development of therapeutic solutions.

PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

“…The targeted NGS testing is unable to exclude or reduce the possibility of unknown gene contributions. Thus, in our opinion it would be advisable to use retinal gene-targeted NGS for genetic diagnosis in any patient, even though the index case belongs to a large family with a known mutation, because this may help identify modifying genes to better explain phenotype–genotype correlations, which must be studied in the future to devise a successful therapy [ 31 ]. Nevertheless, targeted NGS gene panel could not be comprehensive enough to identify phenotype modifying variants in unknown genes.…”

Childhood-onset genetic cone-rod photoreceptor diseases and underlying pathobiology

“…It is expressed in photoreceptors predominantly at the base of the outer segments in the protrusions of disk membranes ( Fig. 3 a) [35] , [36] , [37] . Prominin-1 interacts with cadherin related family member 1 (CDHR1) and actin to promote normal photoreceptor disk morphology [38] .…”

“…PRPH2: PRPH2 (previously known as RDS) encodes peripherin 2 (PRPH2), a photoreceptor-specific tetraspanin membrane protein vital to OS disk morphogenesis, stability and maintenance in rods and cones [36 , 37] . The protein is composed of four transmembrane domains, two intradiscal loops, the D1 and D2 loops, and cytoplasmic N and C termini.…”

“…3 a) [36] . PRPH2 disease has genetic and phenotypic heterogeneity [36 , 37 , 46] . In CORD patients, mutations are most often associated with autosomal dominant inheritance [36 , 46] .…”

Absence of Genotype/Phenotype Correlations Requires Molecular Diagnostic to Ascertain Stargardt and Stargardt-Like Swiss Patients

“…Peripherin 2 is specifically located to the rim region of cone and rod outer segment discs, where it forms complexes with its non-glycosylated homolog ROM-1 (rod outer segment membrane 1) [21]. As peripherin-2 is required for the morphogenesis of the photoreceptors' outer segments, its deficiency leads to cell disorganization and eventually apoptosis [22,23].…”