The PRPH2 gene encodes the protein Peripherin-2 and consists of 3 exons located on Chromosome 6p21. The protein is membrane-associated glycoprotein crucial for photoreceptor outer segment function.
The
PRPH2 L185P variant is located in the second intradiscal loop of the protein, the portion of the protein where over 70% of disease-causing variants are located. This loop is vital to the formation of
PRPH2 homotetramers and
PRPH2/
ROM1 heterotetramers, the impairment of which results in abnormal disc morphogenesis, photoreceptor degeneration, and subsequent visual loss.
58,59 Another study showed that when the
PRPH2 L185P was expressed by itself in COS-1 cells, it was unable to form homotetramers, but when expressed along with wild type ROM1 protein, the
PRPH2 L185P mutant proteins were still able to form heterotetramers.
60 These heterotetramers are involved in the formation of a higher-order complex that extends over the entire circumference of the disc.
61 The individuals in this study have the
PRPH2 L185P variant but are wild type at the positions in
ROM1 known to cause digenic RP. We hypothesize that individuals who carry
PRPH2 L185P are able to form heterotetramers with
ROM1, but are unable to form the higher-order complexes consisting of both homo- and heterotetramers.
61 This inability to form homotetramers, and in turn higher-order complexes, may result in the manifestations of PD seen in Pedigree A and four independent cases. Modifier genes could also explain variable phenotypes and different penetrance in patients with the same variant described in this study.
The other variant described in this report,
PRPH2 c.828+3A>T, is a splice-site variant located between the second and third exons and leads to the addition of 10 amino acids to exon 2 and then a stop codon is encountered. This premature stop results in the last exon being absent from the protein. This last exon encodes the final piece of the protein that is located within the discal membrane and the C terminal of the protein that is in the cytoplasmic space. So, this variant leads to the formation of a nonfunctional truncated protein. It is considered pathogenic as per reports in ClinVar and HGMD.
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