A joint Spanish and Israeli study, conducted by investigators from the Fundacion Jimenez Diaz University Hospital (IIS-FJD, UAM), Madrid, and the Israel Institute of Technology in Haifa, has shown that mutations in the SCAPER gene give rise to a syndromic recessive form of retinitis pigmentosa (RP) manifesting in both retinal degeneration and mental retardation. Whole exome sequencing (WES) was conducted in affected members of Israeli and Spanish families that segregated with autosomal recessive RP and intellectual disability. According to the researchers, over 40 different forms of syndromic RP are documented of which at least 19 include intellectual disability/psychomotor retardation.
The results of the study found that all participants with RP and intellectual disability harboured bi-allelic SCAPER mutations, with patients exhibiting typical RP in addition to mild or moderate intellectual disability and attention-deficit / hyperactivity disorder, but no other symptoms. The SCAPER gene product was found to be widely expressed across a range of human tissues, while animal studies of the corresponding gene showed that the transcript was expressed as early as embryonic day 14 and was located in multiple retinal layers, including the retinal pigment epithelium (RPE), photoreceptor outer and inner segments, the inner plexiform layer and the ganglion cell layer.
The SCAPER gene encodes the S-phase cyclin A-associated protein in the endoplasmic reticulum. The gene is comprised of 34 exons and may have at least two alternatively spliced isoforms. The exact molecular mechanism of pathology for the combined RP and intellectual disability phenotype has yet to be determined however, separate studies have shown that in certain mammalian cells, the SCAPER protein appeared to sequester cyclin A from the nucleus leading to an accumulation of cells in M phase, while depleting SCAPER from cells appeared to decrease the cytoplasmic pool of cyclin A and delay the G1/S phase transition in the cell cycle. As such, SCAPER may be considered a regulatory protein involved in cell cycle division and progression however, it is not clear how such biochemistry may impact on the functioning of fully mature post-mitotic photoreceptor cells. Further research to investigate other SCAPER protein interactions may likely shed further light on the specific pathology. Regardless of the molecular mechanisms in play, the research has established that mutations detected in four patients from three unrelated families of differing ethnic backgrounds, clearly establish the involvement of the SCAPER gene in the aetiology of autosomal recessive syndromic RP.