• retinitis pigmentosa 13

This report describes retinitis pigmentosa 13 (RP13), which is a subtype of retinitis pigmentosa; RP13 exhibits autosomal dominant inheritance. The gene implicated in this disease is PRPF8, a highly conserved component of spliceosomes. There is a single orthologous gene in Drosophila, Prp8, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The human PRPF8 gene has not been introduced into flies.

RP13 is one of several autosomal dominant subtypes of retinitis pigmentosa associated with genes involved in pre-mRNA splicing. A second example studied in flies is retinitis pigmentosa 11 (FBhh0000200). One of the interesting questions is how genetic perturbations affecting core splicing factors manifest in tissue-specific pathogenesis rather than a systemic disease.

Missense mutations analogous to disease-implicated variants in the human gene have been created in Dmel\Prp8 and introduced into UAS constructs. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): S2178F in the fly Prp8 gene (corresponds to S2118F in the human PRPF8 gene); P2361P in the fly Prp8 gene (corresponds to P2301T in the human PRPF8 gene); F2374L in the fly Prp8 gene (corresponds to F2314L in the human PRPF8 gene); H2369P in the fly Prp8 gene (corresponds to H2309P in the human PRPF8 gene); H2369R in the fly Prp8 gene (corresponds to H2309R in the human PRPF8 gene); R2370G in the fly Prp8 gene (corresponds to R2310G in the human PRPF8 gene); R2370K in the fly Prp8 gene (corresponds to R2310K in the human PRPF8 gene); R2370S in the fly Prp8 gene (corresponds to R2310S in the human PRPF8 gene); Y2395N in the fly Prp8 gene (corresponds to Y2334N in the human PRPF8 gene). All nine tested mutations are within the C-terminal Jab1/MPN domain.

Using different GAL4 drivers, phenotypic effects in several different tissues and stages have been assessed for each of the analogous variants. The pathogenicity of the analogous Prp8 Drosophila mutations correlates with the severity of clinical phenotypes in patients carrying the equivalent mutations. In the developing eye primordium, uncommitted epithelial precursors rather than differentiated photoreceptors appear sensitive to Prp8 malfunction; the affected tissue mounts stress and cytoprotective responses. Results in flies support the hypothesis that pathogenicity may result from dominant-negative or gain-of-function mechanisms, rather than from haploinsufficiency.

[updated Aug. 2020 by FlyBase; FBrf0222196]