Abstract
Genetic mutations are frequently associated with diverse phenotypic consequences, which limits the interpretation of the consequence of a variation in patients. Mutations in the retinitis pigmentosa 2 (RP2) gene are associated with X-linked RP, which is a phenotypically heterogenic form of retinal degeneration. The purpose of this study was to assess the functional consequence of disease-associated mutations in the RP2 gene using an in vivo assay. Morpholino-mediated depletion of rp2 in zebrafish resulted in perturbations in photoreceptor development and microphthalmia (small eye). Ultrastructural and immunofluorescence analyses revealed defective photoreceptor outer segment development and lack of expression of photoreceptor-specific proteins. The retinopathy phenotype could be rescued by expressing the wild-type human RP2 protein. Notably, the tested RP2 mutants exhibited variable degrees of rescue of rod versus cone photoreceptor development as well as microphthalmia. Our results suggest that RP2 plays a key role in photoreceptor development and maintenance in zebrafish and that the clinical heterogeneity associated with RP2 mutations may, in part, result from its potentially distinct functional relevance in rod versus cone photoreceptors.
Highlights
Recent advances in whole genome sequencing and exome capture techniques have exploded the field of identification of new disease in patients with genetic diseases [1,2]
As retinitis pigmentosa 2 (RP2) is proposed to function as an activator of small GTPase ADP-ribosylation factor like-3 (ARL3) and may be involved in membrane trafficking, it is critical to examine the effects of mutations in photoreceptors
Our results indicate that involvement of rod versus cone photoreceptors in RP2-associated retinopathy depend upon the specific protein interactions and signaling pathways that are affected by a particular mutation in the RP2 gene
Summary
Recent advances in whole genome sequencing and exome capture techniques have exploded the field of identification of new disease in patients with genetic diseases [1,2]. Even patients with mutations in the same gene frequently exhibit immense clinical heterogeneity, ranging from early-onset disorders to relative less severe late onset disease. Such phenomena pose a challenge to computationally predict and interpret the effect of the mutation on the penetrance and severity of disease phenotypes. Photoreceptors are polarized neurons with a distinct inner segment (IS) and photoreceptive outer segment (OS), linked by a narrow bridge-like microtubule-rich structure, called connecting cilium [3] Proteins, such as rhodopsin, destined for outer segments are synthesized in the IS and are transported via trans-Golgi network to the base of cilium from where they are transported apically by microtubulebased motor assemblies [4]. Owing to high degree of protein trafficking demands, dysfunction in protein synthesis, sorting or trafficking results in photoreceptor dysfunction and degenerative disorders [8]
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