Background Retinitis pigmentosa (RP) shows substantial genetic heterogeneity. It has been estimated that in approximately 60%–80% of RP cases, the genetic diagnosis can be found using whole exome sequencing (WES). In this study, the purpose was to identify causative variants in individuals with genetically unexplained retinal disease, which included one consanguineous family with two affected siblings and one case with RP.
Methods To identify the genetic defect, WES was performed in both probands, and clinical analysis was performed. To obtain insight into the function of KIAA1549 in photoreceptors, mRNA expression, knockdown and protein localisation studies were performed.
Results Through analysis of WES data, based on population allele frequencies, and in silico prediction tools, we identified a homozygous missense variant and a homozygous frameshift variant in KIAA1549 that segregate in two unrelated families. Kiaa1549 was found to localise at the connecting cilium of the photoreceptor cells and the synapses of the mouse retina. Both variants affect the long transcript of KIAA1549, which encodes a 1950 amino acid protein and shows prominent brain expression. The shorter transcript encodes a 734 amino acid protein with a high retinal expression and is affected by the identified missense variant. Strikingly, knockdown of the long transcript also leads to decreased expression of the short transcript likely explaining the non-syndromic retinal phenotype caused by the two variants targeting different transcripts.
Conclusion In conclusion, our results underscore the causality of segregating variants in KIAA1549 for autosomal recessive RP. Moreover, our data indicate that KIAA1549 plays a role in photoreceptor function.
- clinical genetics
- molecular genetics
- vision research
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Contributors SEdB performed sequencing analyses, RNA expression and protein localisation studies. SKV, CBH and LIvdB collected clinical cases and performed clinical examinations of patients. SEdB, EdV, HK, FPMC and SR contributed significantly to design of the study. SEdB, SKV and SR wrote the manuscript. All authors reviewed and approved the manuscript.
Funding The study was financially supported by DCN Radboudumc grant (to FPMC and HK), as well as the Rotterdamse Stichting Blindenbelangen, the Stichting Blindenhulp, the Stichting tot Verbetering van het Lot der Blinden and the Stichting Blinden-Penning (to FPMC and SR)
Competing interests None declared.
Patient consent Not required.
Ethics approval This study was approved by the Institutional Review Boards of the participating centres.
Provenance and peer review Not commissioned; externally peer reviewed.